Carbohydrate-Processing Enzymes of the Lysosome

CHAPTER FOUR

Carbohydrate-Processing Enzymes of the Lysosome: Diseases Caused by Misfolded Mutants and Sugar Mimetics as Correcting Pharmacological Chaperones € tz, Tanja M. Wrodnigg Arnold E. Stu Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Graz, Austria

Dedicated to the Memory of Prof. Dr. Derek Horton

Contents 1. Introduction 2. Carbohydrate-Processing Enzymes of the Glycosphingolipid Degradation Pathway 2.1 Lysosomal β-D-Galactosidase 2.2 Lysosomal N-Acetyl-β-D-hexosaminidase 2.3 Lysosomal α-D-Galactosidase 2.4 Arylsulfatase A 2.5 Lysosomal β-D-Galactocerebrosidase 3. Lysosomal Glycogen Degradation and Glycogen Storage Disease 3.1 Lysosomal α-D-Glucosidase 4. Enzymes of the Glycoprotein Degradation Pathway and Glycoproteinoses 4.1 Lysosomal α-L-Fucosidase 4.2 Neuraminidase 1 4.3 N-Acetyl-α-D-galactosaminidase 4.4 Lysosomal α-D-Mannosidase 4.5 Lysosomal β-D-Mannosidase 4.6 Aspartyl-N-acetyl-D-glucosaminidase 5. Enzymes Involved in Mucopolysaccharide Degradation and Mucopolysaccharidoses 5.1 Lysosomal α-L-Iduronidase 5.2 Lysosomal Heparan-N-sulfatase 5.3 Lysosomal N-Acetyl-α-D-glucosaminidase Advances in Carbohydrate Chemistry and Biochemistry, Volume 73 ISSN 0065-2318 http://dx.doi.org/10.1016/bs.accb.2016.08.002

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2016 Elsevier Inc. All rights reserved.

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5.4 Heparin Acetyl-CoA:α-D-glucosaminide-N-acetyltransferase 5.5 Lysosomal N-Acetyl-D-glucosamine-6-sulfatase 5.6 Lysosomal N-Acetyl-D-galactosamine-6-sulfatase 5.7 N-Acetyl-D-galactosamine-4-sulfatase (Arylsulfatase B) 5.8 Lysosomal β-Glucuronidase 5.9 Lysosomal Hyaluronidase 6. Conclusions and Outlook References

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ABBREVIATIONS 6S-NBI-DGJ 5N,6S-(N 0 -butyliminomethylidene)-6-thio-1-deoxygalactonojirimycin 6S-NBI-GJ 5N,6S-(N 0 -butyliminomethylidene)-6-thio-galactonojirimycin AGA aspartylglucosaminidase, N(4)-(β-N-acetylglucosaminyl)-L-asparaginase AGAL human α-galactosidase ARSA arylsulfatase A ARSB arylsulfatase B, N-acetylgalactosamine-4-sulfatase Asn asparagine BMT bone marrow transplantation CHO Chinese hamster ovary DGJ 1-deoxy-D-galactonojirimycin DGJNAc 2-N-acetyl-2,5-diamino-1,2,5-trideoxy-1,5-imino-D-galactitol DLHex-DGJ methyl 6-{[N 2 -dansyl-N 6-(1,5-dideoxy-D-galactitol-1,5-diyl)-L-lysinyl]amino} hexanoate DMJ 1,5-dideoxy-1,5-imino-D-mannitol DNJ 1,5-dideoxy-1,5-imino-D-glucitol, 1-deoxynojirimycin ER endoplasmatic reticulum ERAD endoplasmic reticulum-associated protein degradation ERT enzyme-replacement therapy FDA US Food and Drug Administration FUCA1 lysosomal α-L-fucosidase GAA lysosomal α-D-glucosidase GALC lysosomal β-D-galactocerebrosidase GalNAc N-acetyl-D-galactosamine GALNS N-acetylgalactosamine-6-sulfatase GBA glucocerebrosidase GH glycohydrolase GLB lysosomal β-D-galactosidase GlcNAc N-acetyl-D-glucosamine GNS, N-acetyl-D-glucosamine-6-sulfatase GUSB lysosomal β-D-glucuronidase HEX A human N-acetyl-β-D-hexosaminidase A HEX B human N-acetyl-β-D-hexosaminidase B HGMD® Human Gene Mutation Database HGSNAT acetyl-CoA:heparan-α-D-glucosaminide N-acetyltransferase HSCT hematopoietic stem-cell transplantation

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HYAL lysosomal hyaluronidase IDUA lysosomal α-L-iduronidase kDa molecular mass in 1000 Daltons LAMAN lysosomal α-D-mannosidase MANBA lysosomal β-D-mannosidase MGAM human intestinal maltase-glucoamylase mM millimolar μM micromolar (106 molar) MPS mucopolysaccharidosis NAGA N-acetyl-D-galactosaminidase NAGLU N-acetyl-α-D-glucosaminidase NBT-DGJ N-(N 0 -butylthiocarbamoyl)-1-deoxygalactonojirimycin NEU neuraminidase NINDS National Institute of Neurological Disorders and Stroke NGT NAG-thiazoline, (2-acetamido-2-deoxy-α-D-glucopyranosyl)-20 -methyl-[2,1-d]Δ20 -thiazoline nM nanomolar (109 molar) NOEV N-octyl-4-epi-β-valienamine OGA O-GlcNAcase, 3-O-(N-acetyl-D-glucosaminyl)-L-serine/threonine N-acetylglucosaminyl hydrolase OMIM Online Mendelian Incidence in Men PDB Protein Data Base code PUGNAc O-(2-acetamido-2-deoxy-D-glucopyranosylidenamino) N-phenylcarbamate SGSH N-sulfoglucosamine sulfohydrolase SRT substrate reduction therapy

1. INTRODUCTION The lysosome is not only the waste-processing and recycling organelle in the cell, but it is also a part of a larger network of endocytosis, autophagy, and salvage processes, termed the “greater lysosomal system.”1 The term “lysosome” dates back to 1955 when this organelle and its function in the “lysis” of biological macromolecules were discovered.2 It contains a large variety of hydrolases that are responsible for the digestion of macromolecules including glycolipids, glycoproteins, and homo- and heteroglycans, just to mention structures where carbohydrates are involved. More than 50 hydrolases create a formidable set of degradation cascades, which, in a highly ordered sequential manner, break down these complex structures into the respective monomers or various building blocks for recycling. Mutations in genes encoding for lysosomal carbohydrate-processing enzymes may cause the formation of misfolded proteins in the endoplasmatic reticulum that subsequently are targeted for recycling by the cell’s quality control

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mechanisms and never reach the lysosome or may lead to catalytically incompetent mutants that arrive in the lysosome but are unable of processing their substrates at physiologically significant levels. Either scenario results in substrate deposits in the lysosome and disturbed feed-forward cycles by the downstream lack of all other consecutive intermediates and final degradation products. Such enzyme deficiencies lead to a group of rare diseases collectively coined as lysosomal storage disorders following a concept initially proposed by Hers in 1963.3 Depending on the respective mutation and its influence on the availability or functionality of the enzyme, the disease may follow different patterns. Early-onset or infantile forms exhibit the worst symptoms and may cause death of the patient within the first months or years of life, whereas more attenuated juvenile or late-onset adult cases are usually characterized by less rapid disease progress and milder symptoms. In addition, for quite a few of these diseases, an unknown number of cases may remain undetected with atypical or unrecognized symptoms. Despite the fact that due to their rarities (typically 1:40,000 to 1:1,000,000), lysosomal storage disorders have the orphan disease status, their combined incidence may range around 1:6000 to 1:8000 live births.4,5 To place these numbers into perspective, a comparison with diseases more present in the media and better known to the general public shows, for example, that for well-known Creutzfeldt–Jakob prion disease, also casually coined “mad cow disease” by the media, there have been 176 cases recorded in Great Britain between 1994 and 2011. For Germany, estimations of 100 new cases per year have been mentioned with three times as many in the United States. Among 70-year-olds it is estimated to affect 1 in 125,000 persons of this age-group world-wide. Epidermolysis bullosa, the well-publicized “butterfly disease,” a hereditary disease of the connective tissues, has an incidence of 1 in 20,000–50,000 children. In another example, each year 1 in 35,000 inhabitants world-wide may acquire the malignant brain tumor, glioblastoma. Several approaches have been explored to cure or ameliorate lysosomal disease symptoms and to improve patients’ and their families’ lives. Enzyme-replacement therapy (ERT)6,7 involves biweekly infusions of recombinant enzyme at various dosages, depending on the disease and inherent side effects. Bone disease symptoms such as in Gaucher disease are apparently not reversible, and the blood–brain barrier has remained a problem for ERT of quite a few lysosomal disorders with a neuronopathic course. Substrate reduction therapy (SRT)8,9 involves the application of reversible small-molecule inhibitors to reduce the upstream formation of the compromised enzyme’s substrate.

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Other, less frequent or experimental treatment methods include bone marrow transplantation (BMT), hematopoietic stem-cell transplantation (HSCT), and gene therapy,10,11 the latter having reached clinical stages. Recently, proposed chaperone-mediated therapy (CMT) has become an area of great hope and, consequently, the subject of many intense research endeavors. As early as 1977, Dugal speculated that “any compounds that could be used to activate the enzyme (1-aspartamido-β-N-acetylglucosamine amidohydrolase) and thus help eventually to control the incurable disease (aspartylglucosaminuria, one of the lysosomal glycoprotein degradation disorders) may be of some use from a clinical point of view.”12 Early hypotheses of “enzyme manipulation therapy” were proposed by Desnick and coworkers.13,14 The current concept of CMT was established by Fan and coworkers15 and has met with considerable attention since. This therapeutic approach16–30 relies on the application of small, activesite-specific molecules, usually (but not in all cases) powerful competitive inhibitors of the enzyme under consideration, which, in subinhibitory concentrations, support the correct folding of the therapy-susceptible, freshly synthesized enzyme mutant and its transport from the ER to the lysosome, bypassing the ERAD shunt of quality control and degradation. There, by diffusion or pH change, most such inhibitors easily exit the active site, which is now available for the respective substrate, albeit at lower turnover numbers than in the corresponding “healthy” wild-type enzyme. As a currently accepted rule of thumb, an activity increase of threefold and an activity of at least 10% of the wild type are the thresholds for a positive chaperone effect as would be required at minimum for homeostasis and reduction of substrate deposits. With several dozens to well over a hundred disease-causing mutations each, any one of which influences the intensity and the progress of the respective disease, lysosomal storage disorders, scientifically, may serve as a paradigmatic example for “personalized medicine.” This reflects nicely when the different effects of individual pharmacological chaperones on the activity of a particular enzyme mutant are compared. Moreover, strong evidence has been accumulating that lysosomal disorders may just be the visible tip of the proverbial iceberg of effects triggered by dysbalances or failures in individual “process lines” of the greater lysosomal system on (human) health and metabolic diseases. For example, over the past five years, an overwhelming chain of pieces of evidence has clearly established a firm connection between mutations in the Gaucher-related GBA1 gene and Parkinson’s disease as well as Lewy body dementia. It could be demonstrated that GBA mutants promote α-synuclein accumulation by reduced lysosomal function

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in a dose- and time-dependent manner, whereby lack of glucocerebrosidase activity initially led to neuronal ubiquitinopathy and axonal spheroids.31–44 In a mouse model, downregulation of autophagy, mitophagy, and ubiquitin–proteasome system resulted in dysfunctional mitochondria, insoluble α-synuclein deposits, and ubiquitinylated proteins.45 Interestingly, it was found that carriers of the frequent N370S mutation are at lesser risk of Parkinsonism,46 while L444P was found to be associated with early-onset Parkinson’s,47 and E326K was found to predispose to Parkinson’s disease but does not cause Gaucher’s.48 Similarly, the connection between Alzheimer’s disease and the manifold effects of GM1-ganglioside49 metabolism has recently also attracted considerable interest50–55 and has led to the conclusion that “….Alzheimer’s disease is beginning to emerge as a neurodegenerative disorder that may share similarities in terms of underlying pathogenic mechanisms with lysosomal disorders.”56 In the light of these developments, research into rare lysosomal disorders may also have significant impact on common age-related diseases such as Alzheimer’s (world-wide 29 million cases in 2007), Parkinson’s (estimated 53 million cases globally in 2013), as well as others. Not surprisingly, the overwhelming majority of pharmacological chaperones investigated in context with lysosomal storage diseases of glycoconjugate and glycan catabolism are carbohydrate mimetics, and of these, practically exclusively carba- and imino-sugar types have been utilized thus far.18,20,26 In the area of sugar analogs with nitrogen in the ring, imino sugars and isoimino sugars, for example, 1-deoxynojirimycin [1,5-dideoxy-1,5imino-D-glucitol (1, Fig. 1)], its epimers, and their derivatives as well as isofagomine (4), have found broad interest based on their plentiful and potent biological activities that have competently been reviewed at several points in the past.57–62 In the realm of carba sugars63,64 (formerly coined “pseudo sugars”65), various derivatives of valienamine, a constituent of the validamycin-type R H N

N HO

OH

HO HO

OH

HO HO

OH

OH 1: R = H 2: R = Butyl

OH 3

NH HO

NHC8H17

HO HO

OH 4

Fig. 1 Carba and imino sugar-derived glycosidase inhibitors 1–5.

OH OH 5

Carbohydrate-Processing Enzymes of the Lysosome

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natural products, have been investigated. In particular, N-octyl-4-epi-βvalienamine (NOEV, 5) has been considered a bench mark as β-galactosidase inhibitor and pharmacological chaperone with impressive properties. In this review, we have attempted to look at lysosomal enzymes from the position of carbohydrate chemists emphasizing carbohydrate mimicking structures as potential pharmacological chaperones and inhibitors, thus focussing exclusively on carbohydrate-processing enzymes. Glucocerebrosidase/ Gaucher disease has been excluded from this work due to the large number and high quality of available books66–68 and review articles69–76 already covering this topic in great detail. On the other end of the scale, mucolipidoses, diseases involving GlucNAc modification, are not covered due to lack of available pieces of information in context with the aim of this chapter. Furthermore, as nonexperts on the medical side, we have limited the listing of disease symptoms to a minimum wherever possible. Many electronic sources provide such pieces of information more conveniently and comprehensively than this account would have been able to. In context with lysosomal β-galactosidase, Morquio B disease has been treated together with GM1gangliosidosis due to same enzyme being involved in both disorders.

2. CARBOHYDRATE-PROCESSING ENZYMES OF THE GLYCOSPHINGOLIPID DEGRADATION PATHWAY 2.1 Lysosomal β-D-Galactosidase Human lysosomal β-galactosidase (EC 3.2.1.23) is a retaining GH 35 exoglycosidase which removes the outermost β-galactopyranosyl residue from the gangliosides GM1 and GA1, thus providing GM2 and GA2 gangliosides as substrates for hexosaminidases A and B in the next degradation step (Scheme 1).78 The protein exists in two isoforms (76 kDa, 677 amino acids; 60.5 kDa, 546 amino acids) and has seven possible N-glycosylation sites, two of which are indeed glycosylated (N464, N555). The encoding gene (GLB1) is located on chromosome 3 (3p21.33).79 The enzyme forms a complex with α-neuraminidase and lysosomal protective protein/cathepsin A.80 Eight single-crystal X-ray structures of human lysosomal β-galactosidase are available: In 2012, Shimizu and coworkers provided the structures of the protein complex with D-galactose (PDB 3THC) as well as of the complex (PDB 3THD) with the powerful D-galactosidase inhibitor 1-deoxy-Dgalactonojirimycin (DGJ, 1,5-dideoxy-1,5-imino-D-galactitol (6), Fig. 2).81

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: Glc α3 β3

β4

β4

β-Cer

: GalNAc

GM1

: Gal β-D-Galactosidase : Neu5NAc

α3 β4 β3

β4

β4

β4

β-Cer

GM2

GA1

β-Cer

N-Acetyl-β-D-hexosaminidase α3

β-D-Galactosidase β4

β4

β-Cer

GA2

β4

β-Cer

β4

β-Cer

GM3 Neuraminidase I

N-Acetyl-β-D-hexosaminidase

β-D-Galactosidase

3S β-Cer

β-Cer S

Arylsufatase A

β-Cer

β-D-Glucocerebrosidase

β-D-Galactocerebrosidase Cer

Scheme 1 Glycosphingolipid degradation pathways. Modified from Varki et al.77

N O S O

NH

O H N

R N

N

HO

O

HO O HO

OH

HO

OH

OH OH

6: R = H 7: R = C4H9

8

H N HO

O HO

dansyl N H

N

OH OH 9

Fig. 2 β-D-Galactosidase inhibitors 6–9.

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Carbohydrate-Processing Enzymes of the Lysosome

N

N

S

S

S N

HO

N

OH

HO

OH

OH

HO

N

HO

N H OH

OH

OH

OH

10

11

12

Fig. 3 β-D-Galactosidase inhibitors 10–12.

Together with their Spanish collaborators, the structures of the enzyme with the benchmark chaperone carbasugar NOEV (5) (PDB 3WEZ) and with imino sugars 6S-NBI-DGJ (10) (3WF0; Fig. 3), 6S-NBI-GJ (11) (PDB 3WF1) and with NBT-DGJ (12) (3WF2) were published in 2014.82 Furthermore, crystal structures of the enzyme mutant I51T (which is frequently found among GM1-gangliosidosis patients in Japan) in complex with compound 10 (PDB 3WF4) and with D-galactose (PDB 3WF3) have been reported.82 Transportation-challenged or catalytically incompetent β-D-galactosidase mutants are associated with GM1-gangliosidosis (and with Morquio B disease, a mucopolysaccharidosis). More than 160 such mutations are known to date.83 GM1-gangliosidosis (Online Mendelian Incidence in Men: Phenotype: #230500, type I, infantile; #230600, type II, juvenile; #230650, type III, adult) and Morquio B disease (OMIM #253010, 1 of 11 mucopolysaccharidoses) are caused by mutation of the GLB1 gene at chromosome 3 (3p21.23) and characterized by the absence of catalytically competent β-galactosidase. Type I is a neurosomatic disease with rapidly progressing neurological deterioration, visceromegaly, and generalized dysostosis. More attenuated juvenile and adult forms present progressive neurological disease in childhood or early adulthood caused by predominant storage of glycolipids in neuronal tissues with minor or absent dysmorphic changes.84 Neuronal damages are not primarily caused by deposition of unprocessed GM1 ganglioside but by secondary effects to the unfolded protein resulting in the upregulation of chaperones and apoptotic factors.85 Whereas GM1-gangliosidosis is a neurodegenerative disorder, Morquio B is caused by the lack/failure of this β-galactosidase in the degradation cycle of glycosaminoglycans and is mainly associated with bone damage (“skeletal phenotype”). In case of some mutations, it is currently still impossible to predict the phenotype—neuronal damage vs bone damage—from the genotype.86

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GM1-gangliosidosis is estimated to occur in 1:100,000 births with considerably higher incidence in isolated communities, for example, in southern Brazil (1:13,000)87 or Malta (1:3700).88 Estimations based on these values would account for 400–600 cases in Germany, somewhat fewer in France and Spain, about 2000 cases in the United States, 1000 in Japan as well as in Russia, and more than 10,000 each in China and India. For both, Morquio B disease and GM1-gangliosidosis, there is currently no cure available. Traditional treatment includes attempted relief from pain and reducing symptoms as well as family counseling. Contrary to nonneuronopathic disorders, for example, certain forms of Gaucher’s (catalytic incompetence of β-glucocerebrosidase) as well as Fabry’s disease (α-galactosidase activity deficit), for which approved recombinant enzyme preparations are available,89 ERT with recombinant human β-galactosidase is currently not readily feasible due to the inherent difficulty of trafficking the enzyme through the blood–brain barrier for sufficient concentration in the brain. Such a current lack of applicability also holds true for gene therapy. SRT has been introduced for other lysosomal storage diseases including Gaucher’s [for example, Zavesca® or Miglustat, N-butyl-1deoxynojirimycin (2)], but has not become as advanced for GM1gangliosidosis, where it has remained being proven in a mouse model with only two compounds, 7 and 2, thus far.90,91 Consequently, great hope is currently focused on the concept of CMT. Several D-galactosidase inhibitors have been evaluated as potential pharmacological chaperones for GM1-gangliosidosis and Morquio B-related mutants. In particular, two main structural types, a carba sugar motif as well as a series of DGJ-related imino sugar derivatives, have been investigated. In 2001, Nanba and coworkers found that DGJ (6) as well as its N-butyl derivative 7 at concentrations of 500 μM increased β-galactosidase activities in mouse fibroblasts.92 In mutant reference cell lines R201C (juvenile) and in R457Q (adult), these increases were 5.5–6-fold for compound 6 and 4.8–5.4-fold for 7. In addition, the latter inhibitor provided a 6.1-fold increase of enzymatic activity in the I51T (adult) cell line, a frequently occurring mutation in Japan. Increases of β-galactosidase activity were also noted with human cell lines. By various modifications of the spacer arm and the terminal substituent, considerable activity enhancements could be achieved. For example, a compound coined DLHex-DGJ (8) (Ki 0.6 μM), showed significant activity enhancements (5–6-fold) with chaperone-sensitive R201C as well as R201H cell lines at 20 μM and up to 18-fold increases at 500 μM.93 Derivative 9 (Ki 0.7 μM), bearing the

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Carbohydrate-Processing Enzymes of the Lysosome

dansyl moiety at the terminus of the extended spacer arm, gave nearly a 6-fold activity increase with R201C at 10 μM and 9- to well over 10-fold increase between 20 and 500 μM.94 Compounds with fluorous substituents such as 13 (Fig. 4) and 14 (Ki 0.8 μM, each) showed similar effects at 5–20 μM (4–5-fold increases of activity with R201C). Furthermore, R201H and C230R mutants reacted favorably to both compounds with increases of 9–10-fold at 10 μM.95 Noteworthy in this context was the pronounced onset of inhibition at concentrations higher than 50 μM pointing to a wider “therapeutic window” of compounds in the dansyl-capped series. Powerful effects were reported for N-nonyl-DGJ (15) (Ki 0.18 μM) in two R201H cell lines that showed increases of 5- and 7-fold, respectively, at a concentration as low as 1 μM.96 A feline GM1 model reacted analogously at concentrations between 0.7 and 2.1 μM. Other iminoalditol-derived compounds such as chain-extended iminoribitol 16, Fig. 5, (6-fold at 390 μM) were also found to increase the activity of R201C mutants.97 This compound, as well as analogs such as 17 (IC50 100 μM, bovine liver, 2.1-fold with R201C) provided by Martin and collaborators,98 behaves similar to the isoimino sugar and potent inhibitor 4-epi-isofagomine (18, Fig. 6) (IC50 ¼ 0.4 μM, β-galactosidase from

O N HO

CF3 R CF3

HO

OH

N HO HO

OH 13: R = CF3 14: R = Ph

OH OH 15

Fig. 4 β-D-Galactosidase inhibitors 13–15. Ph OH

C6H13 HO

HO

NH HO

NH HO

NH

HO HO

OH

OH

OH

16

17

18

Fig. 5 β-D-Galactosidase inhibitors 16–18.

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H3C

H HCl N R

NHC8H17

HO

OH OH 19

HO

OH OH 20: R = C8H17 21: R = CH2CH(CH2CH3)2 22: R = CH2cyclohexyl

Fig. 6 Carbacyclic β-D-galactosidase inhibitors 19–22.

human leukocyte lysate, 2.7-fold increase with R201C) and thus can be expected to bind in the “isoimino sugar mode.”26 The benchmark molecule for GM1-gangliosidosis chaperones has been a carba sugar and highly potent β-galactosidase inhibitor, NOEV (5) (IC50 ¼ 0.125 μM with human β-galactosidase)99,100 introduced as pharmacological chaperone by Suzuki101 in 2003, which also exhibited blood–brain barrier permeability.102 At concentrations between 0.2 and 2 μM, this notable compound gave activity enhancements of 5.1-fold for R201C and 4.5-fold for R201H cell lines and proved three orders of magnitude more efficient than compounds 6 and 7. In extended studies, more than 20% of 94 screened mutants were found responsive to NOEV chaperoning.103 Various pathogenic proteins were found reduced after NOEV treatment along with extended survival times.104–106 Searching for NOEV derivatives featuring improved pharmacological properties, Kuno and coworkers synthesized, from (+)-proto-quercitol, the 6-deoxy derivative 19 (Fig. 6), which indeed turned out to be a stronger inhibitor (IC50 0.2 μM, bovine liver) than NOEV itself (2.6 μM).107 Recently, from the same starting material, a range of analogs lacking the hydroxymethyl side chain, for example, compounds 20 (IC50 ¼ 120 μM), 21 (IC50 ¼ 15 μM), and 22 (60 μM), were prepared.108 Despite IC50 values that range one to two orders of magnitude higher than NOEVs (1.7 μM), improved chaperoning properties were found with 22 in the lead (8.5-fold with R201C), albeit at 10-fold higher concentration than had to be applied for the parent compound. Following up on their own impressive work on “sp2-iminosugars” of the 109 D-gluco series, Ortiz Mellet and Garcia Fernandez prepared new iminosugar–isothiourea hybrids such as compound 10, which was found to effect a 6-fold enhancement of β-galactosidase activity in the R201C cell

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line, favorably comparing to NOEV, but above concentrations of 100 μM and without toxic side effects up to 640 μM.110 Despite being a weaker inhibitor than NOEV (5), chaperone 10 was active with a broader spectrum of GM1-gangliosidosis mutants than the former including 24 of 88 screened human mutants,111 in particular with I51T, a frequent mutation in Japan, as well as with G438T, both of which are known to be unresponsive to NOEV.102,103 Gratifyingly, the chaperone was found to cross the blood– brain barrier.111 An in-depth investigation into the differences between NOEV (5) and 6S-NBI-DGJ (10) has recently been conducted, revealing a possibly advantageous, more flexible binding mode for the latter, lacking interaction with Tyr133 in the catalytic site.82 Based on Fan and coworkers’ finding that C-5a-chain-extended derivatives of the powerful β-glucosidase inhibitor isofagomine exhibit highly superior inhibitory activities when compared with the parent compound,112 the attempt to transfer this particular structural feature into the D-galacto-related 4-epi-isofagomine series was recently successful. In the (5aS)-series, 5a-dansylaminobutyl-4-epi-isofagomine (23, Fig. 7) turned out to be a powerful inhibitor of β-galactosidases, showing an IC50 value of 0.21 μM with human lysosomal β-galactosidase. A preliminary report on its chaperoning properties revealed a 6-fold activity increase in the R201C cell line at 0.04 μM and a maximum effect of 15-fold increase at 5 μM. At higher chaperone concentrations, inhibitory effects reduced the enhancement gradually to a level of 11-fold at 25 μM.113 In the corresponding (5aR)series, epimer 24 was a weaker inhibitor by one order of magnitude (IC50 ¼ 2.7 μM) and gave a 9-fold enhancement in a concentration range between 20 and 100 μM. Interestingly, analog 25 featuring a two-carbonlonger spacer arm inhibited at a level comparable to compound 23 with IC50 ¼ 0.38 μM. As a chaperone compound 25 showed a 3.5-fold activity increase at 0.02 μM and reached a maximum of 10-fold at 2.5 μM. Similar

NH 2

HO

NH HO

N

NH

S O

n

O HO

N S

O

O

NH HO

OH 23

OH 24: n = 2 25: n = 4

Fig. 7 Isofagomine-related fluorescent β-D-galactosidase inhibitors 23–25.

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to the latter, dose-dependent onset of inhibition gradually reduced the beneficial effect to 9-fold at 12.5 μM.114 Despite the fact that these encouraging values clearly rival NOEV’s high standards, the broader applicability across a range of important and telling mutant cell lines, as well as blood–brain barrier crossing properties of this new compound family, remains to be proven. Thus, for GM1-gangliosidosis/Morquio B, there are now three structurally different types of potent experimental chaperones: The NOEV-type carba sugars, the DGJ derivatives, and analogs including the bicyclic isothioureas, as well as the chain-extended 4-epi-isofagomines.

2.2 Lysosomal N-Acetyl-β-D-hexosaminidase Human N-acetyl-β-hexosaminidase exists as two isoenzymes, Hex A and Hex B, which are encoded by the HEXA (15q23–q24) and HEXB (5q13) genes located on chromosomes 15 and 5, respectively. Hex A is a heterodimer consisting of subunits α and β, which share 60% homology, while Hex B is a homodimer of β-subunits. In concert with a small monomeric cofactor, GM2 activator protein, Hex A (EC 3.2.1.52, GH 20, Mr 112.5 kDa), removes the terminal nonreducing N-acetyl-D-galactosamine (GalNAc) from the GM2 ganglioside.115 Crystal structure data are available for mature lysosomal Hex A (PDB 2GJX) and its complex with N-acetyl-D-glucosamine-derived thiazoline 26 (Fig. 8, PDB 2GK1).116 Structures of native Hex B (1NOU),117 recombinant “near-native” Hex B with 2-acetamido-2-deoxy-D-glucono1,5-lactone (27, 1O7A),118 as well as Hex B in complex with compound 26 (1NP0), with 4-epi-isofagomine-related aminal 28 (1NOW), and with noncarbohydrate pharmacological chaperone pyrimethamine 29 (Fig. 9, 3LMY)119 are also available. Genetically caused deficiencies of either the α- or β-subunit or the activator protein lead to GM2-gangliosidosis, which is subdivided into a group of three lysosomal storage diseases, Tay–Sachs disease (OMIM# 272800, named after British ophthalmologist W. Tay and American neurologist B. Sachs), Sandhoff disease120 (OMIM# 268800), and the AB variant form (OMIM# 272750). Cl O HO

O

S

NH2

O

HO

HO

NH

CH3 N

HO

N HO

NHAc

HO

NHAc

OH

OH

OH

26

27

28

Fig. 8 β-D-N-Acetylhexosaminidase inhibitors 26–29.

H2N

CH3

N 29

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Carbohydrate-Processing Enzymes of the Lysosome

H N

R

HO HO

N

HO

NHAc OH 30: R = OH 31: R = H

HO

R OH 32: R = OH 33: R = NHAc

Fig. 9 β-D-N-Acetylhexosaminidase inhibitors 30–33.

GM2-gangliosidosis is estimated to be about as common as GM1gangliosidosis. Symptoms of the most common variant, late-infantile Tay–Sachs disease may include developmental arrest, neurological deterioration, blindness, and seizures culminating in death at 3–4 years of age.78 Late infantile and juvenile forms of Tay–Sachs and Sandhoff disease are almost indistinguishable. A diagnostically characteristic symptom is the formation of a “cherry-red” spot in the macula by accumulation of ganglioside in the ganglion cells creating a ring of pallor around the center of the macula.78 With established treatment options being scarce, hope and research are currently focussed on gene-transfer therapy, neural stem-cell transplantation as well as chaperone-mediated therapy. Initial investigations into the properties of imino sugars as potential pharmacological chaperones for adult Tay–Sachs and Sandhoff variants were conducted by Mahuran, Withers, and collaborators who screened DNJ (1), 2-N-acetyl-2,5-diamino-D-glucose (30, Fig. 9), the GlcNAc analog of nojirimycin 3, the indolizidine alkaloid castanospermine 32, the corresponding 6-acetamido-6-deoxy derivative 33,121 as well as the thiazolidine NGT 26.122 The transition-state analog NGT turned out the best-suited compound effecting significant increases of HEX A activity in patients’ fibroblasts and exhibiting very low cell toxicity. The Maybridge library of 50,000 compounds was scrutinized in a high-throughput screen resulting in 28 achiral molecules, most of them nitrogen-containing bi- or tricyclic aromatic systems, confirmed to be N-acetyl-β-hexosaminidase inhibitors with Ki values in the low μM range.123 Three of them, compounds 34, 35, and 36 (Fig. 10), did not inhibit other lysosomal enzymes or cytosolic O-GlcNAcase and were further screened with patient fibroblasts producing activity increases of up to 3-fold. Compound 35 acted as a classic competitive inhibitor with a Ki value of 0.8 μM and was deemed a useful lead toward pharmacological chaperones for

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N

O

OH

O H N

O

CH3 Cl

N

HN

N

NH

N+ O–

N O

O O

O 34

35

36

Fig. 10 Recently discovered β-D-N-acetylhexosaminidase inhibitors 34–36.

R N HO

HO

NHAc

37: R = H 38: R = Bn

Fig. 11 Furanoid β-D-N-acetylhexosaminidase inhibitors 37 and 38.

Tay–Sachs and Sandhoff diseases featuring a framework also found in some FDA-approved drugs. Pyrimethamine, 2,4-diamino-5-(4-chlorophenyl)6-ethylpyrimidine (29), another drug-like molecule with established antimalarial activity, was identified by screening the NINDS library of 1040 FDA-approved compounds and was found a good inhibitor (Ki 13 μM at pH 4.5) of Hex A.124 It exhibited beneficial effects with the G269S mutant, which is the most prevalent125 mutation in late-onset adult Tay–Sachs disease. Likewise, various other mutants examined responded to this chaperone with activity enhancements of up to 3-fold. In two cell lines with atypical infantile Sandhoff tested recently, enhancements of hexosaminidase in the presence of compound 29 were found, but GM2 was not converted into GM3.126 In the realm of imino sugars, a wide range of N-acetylhexosaminidase inhibitors have been reported, and quite a few were screened with human β-hexosaminidases from different organs. 2-Acetamido-1,2,4-trideoxy-1,4-imino-L-arabinitol (37)127 (Fig. 11) was employed to induce experimental GM2-gangliosidosis128 and was also one of the first furanoid imino sugars probed as a potential pharmacological chaperone.129 Its N-benzyl derivative 38 was found to initiate a 2-fold increase of enzymatic activity in a concentration range between 5 and 50 μM. No such activity was found with the corresponding D-enantiomer. The selection of potentially viable pharmacological chaperones for Tay–Sachs and Sandhoff diseases has recently been considerably increased

241

Carbohydrate-Processing Enzymes of the Lysosome

by contributions from several workers, including leading groups in the area who have reported novel types of N-acetylhexosaminidase inhibitors based on imino sugars,130–139 carba sugars,140 other sugar analogs,141–143 as well as carbohydrate and noncarbohydrate small molecules144 with a view to improved efficacy and selectivity for lysosomal and other β-hexosaminidases.

2.3 Lysosomal α-D-Galactosidase Lysosomal α-galactosidase (α-galactosidase A, EC 3.2.1.22) is a retaining GH 27 hydrolase responsible for the removal of terminal α-galactosyl residues from the nonreducing end of degradation-bound glycolipids and glycoproteins, in particular from GM2-ganglioside. Mature human α-galactosidase A is a homodimeric glycoprotein with a molecular mass of 101 kDa.145,146 Three of the four potential glycosylation sites (Asn 139, Asn 192, and Asn 215) are indeed glycosylated, and glycosylation at Asn 215 is required for solubility of the enzyme. Human α-galactosidase was crystallized in 1994147 but resisted structural analysis due to the high proportion of and heterogeneity of carbohydrates on the protein.148 The structure of human α-galactosidase was reported in 2004149 (PDB codes 1R46, 1R47) revealing a homodimer containing six glycosylation sites, and the locations of 245 missense and nonsense mutations were mapped on this structure. Since, quite a few additional structures have been reported: The free enzyme at pH 4.5 (PDB 3GXN) as well as its complexes with 150 D-galactose (3GXP) and the inhibitor (Ki 39 nM) DGJ, 6 (3GXT), the empty active site (3HG2) with bound substrate (3HG3), covalent intermediate (3HG4) and bound product (3HG5),151 the enzyme bound to GalNAc (3LX9), D-galactose (3LXA), and glycerol (3LXB, 3LXC)152 the complexes with D-galactose (3S5Z) and DGJ (3S5Y) as well as the D170A mutant coordinated by DGJ (3TV8)153 and, most recently, the complex with an aryl thiourea derivative 39 of DGJ (4NXS, Fig. 12).154 Mutations in the AGAL A gene lead to reduced cellular enzyme activity resulting in Fabry’s disease (OMIM 301500), first described independently S

H N

F

H N

N HO

H N

HO HO

OH

OH HO

OH

H N

HO

OH HO

OH

HO HO

OH

OH

OH

OH

OH

39

40

41

42

Fig. 12 α-D-Galactosidase inhibitors 39–42.

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by Anderson155 and J. Fabry in 1898,156 and nicely reviewed by H. Fabry in 2001.157 It is an X-chromosome (Xq22.1)-associated rare metabolic disease caused by (currently around 600 identified) mutations of the AGAL A gene and is characterized by partial or total lack of lysosomal α-galactosidase A activity. Fabry disease is assumed the second most prevalent lysosomal disorder next to Gaucher’s affecting all ethnic groups with an estimated incidence of 1:40,000 to 1:170,000 births, but it may be more common than these estimations suggest. A study in Italy recently found that 1 in 3200 new-born children showed missense mutations in the α-galactosidase gene, but a large number of these may be phenotypically “silent.”78,158 In other studies, 3–6% of males with cardiomyopathy or left ventricular hypertrophy were diagnosed with Fabry cardiac variants, indicating a much larger abundance of this type of Fabry disease than previously estimated.159 Typical symptoms may affect the vascular system and the heart, the kidneys, as well as the central nervous system. There is also a relatively increased risk of depression associated with the disease.160 Treatment by ERT (agalsidase alfa, “Replagal,” and agalsidase beta, “Fabrazyme”) has been available since 2001, but it requires adjuvant therapies, in particular pain control and monitoring of blood pressure for cardiac function and risk of stroke. Replagal is produced in a human cell line, whereas Fabrazyme is expressed in CHO cells.149,160–164 In 1993, D-galactose and, to lesser extent, melibiose were reported to improve the activity of late-onset Fabry’s associated α-galactosidase mutant Q279E.165 Several other mutants, for example, A156V, L166V, G260A, and G273S, were also found to react positively to the presence of D-galactose at concentrations of 100 mM of this sugar in the culture medium, whereas C142Y, E66Q/R112C, G328R, and N320K did not respond favorably.166 A subsequent case report167 on a 55-year-old male bearing the G328R mutation demonstrated the beneficial activity of D-galactose over a two-year period, after which the man’s health conditions had improved to an extent that an intended heart transplantation was not deemed necessary. For CMT, some small molecules have moved close to the market, and others are in advanced trials or in experimental stages: 1,5-Dideoxy-1,5-imino-D-galactitol (DGJ, 6) was indeed the first compound probed as an experimental pharmacological chaperone for Fabryrelated α-galactosidase mutants. With low concentrations (0.2–20 μM) of this powerful competitive inhibitor (IC50 4.7 nM), noteworthy enzyme activity enhancements for the late-onset mutants R301Q and Q279E of

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up to 8-fold (48% of wild type) and up to 7-fold (45% of wild type), respectively, were recorded.15 Based on this encouraging result, compound 6 and a range of 15 structurally related compounds also including selected Nmodifications were investigated by Fan and collaborators.168 In particular, parent compound 6 and close analog 40 (“α-homo-D-galactonojirimycin,” Fig. 12) exhibited powerful inhibition activity with human lysosomal α-galactosidase (IC50 0.04 and 0.21, respectively). Compounds were screened with R301Q lymphoblasts over a concentration range between 1 and 1000 μM, with inhibitor 6 found to be the most potent experimental chaperone effecting a 14-fold activity increase of this mutant at 100 μM, trailed by homonojirimycin derivative 40 (5.2-fold) and D-allo analog 41 (2.4-fold). For additional information, the binding characteristics of various inhibitors, in particular, DGJ (6) and 5-amino-5-deoxy-D-galactose hydrogen sulfite adduct, were directly compared by isothermal titration calorimetry and surface plasmon resonance biosensor assays.169,170 It could be shown that DGJ (6) corrects the trafficking defect of ER-retained R301Q α-galactosidase A and other trafficking-incompetent variants.171–174 Good to noteworthy enhancements of enzymatic activity at 20 μM were also found with mutants M42V (in COS7 cells, 2.5-fold), I91T (COS7, 2.9fold), A97V (T-cells, 5.5-fold), R112H (T-cells, 20-fold), F113L (COS7, 2.6-fold), A143T (T-cells, 2.2-fold), and L300P (T-cells, 37-fold), whereas others such as 30delG, G132R, A143P, or R220X did not respond to compound 6.175,176 Benjamin, Desnick, and coworkers probed an impressive total number of 75 mutants with patients’ lymphoblasts and found half of the missense mutants associated with early-onset as well as 90% of later-onset variants responsive to DGJ,177 and in a comprehensive study taking advantage of an HEK-293 cell-based assay, this group probed the responsiveness of 80 mutant cell lines toward compound 6.178 As many as 78 responsive mutants were reported in an independent Japanese study.179 Fibroblast and lymphoblast responses were found comparable for the same mutation. The responsiveness of a significant number of Fabry mutations to DGJ was also investigated by Rolfs and collaborators.180 Defining an activity increase of 1.5-fold or >5% as responsive, nearly 43% of the missense mutations were amenable to DGJ-mediated activity enhancement. Based on these data in combination with the monitoring of the biomarker181 plasma lyso-globotriaosylsphingosine accumulation in patients, a classification system was proposed. DGJ was reported to reduce globotriaosylceramide levels in various tissues such as skin, heart, kidney, and brain in a mouse

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model182 for Fabry disease as well as in the plasma of Fabry patients.181 Nonresponsive mutants were shown to lose activity by aggregation phenomena rather than by misfolding-associated loss of function.183 A thermodynamic assay based on the urea-induced unfolding of recombinant α-galactosidase, whereby the effects of pharmacological chaperones such as DGJ on the stabilization of the unfolded protein can be determined, was recently introduced.184 Synergistic effects were found for concomitant application of human recombinant α-galactosidase A and compound 6, underscoring the pharmacological potential of such drug combinations.185 In clinical studies, migalastat (6) was shown to be well tolerated by suitable candidates when administered in oral doses between 50 and 250 mg every other day.186 Successful market introduction is expected for 2016. Due to the initial good results with DGJ, as well as the early industrial background for the pharmaceutical development of this molecule, and disregarding the early investigation of several analogs and epimers of DGJ,168 derivatives and other potential pharmacological chaperones for Fabry’s disease-related α-galactosidase A mutants are scarce. Besides DGJ, only a few other compounds have recently been scrutinized. Fleet and collaborators introduced the L-enantiomer of 1-deoxygalactonojirimycin (42, Fig. 12) conveniently prepared from D-tagatose, as a noncompetitive inhibitor (Ki 38.5 μM) of lysosomal α-galactosidase A. Compared to DGJ, this by three orders of magnitude reduced inhibitory activity translated into a chaperoning effect of 10.8-fold at 10 mM. Interestingly, these workers found synergistic effects when applying both enantiomers together in a ratio of 1:100 (D:L).187 The five-membered ring 2,5-dideoxy-2,5-imino-D-altritol (43, Fig. 13), isolated from roots of Adenophora triphylla (Japanese lady bell), was investigated in 2010 and shown to exhibit a Ki value of 0.5 μM. It was found O O S H N

HN H N

F

S

OMe

N

N

HO

OH

O

HO HO

OH OH

43

S N

OH HO

HO

H N

44

Fig. 13 α-D-Galactosidase inhibitors 43–46.

HO

OH OH 45

HO

OH OH 46

C4H9

Carbohydrate-Processing Enzymes of the Lysosome

245

to increase the intracellular α-Gal A activity in Fabry R301Q lymphoblasts by 9.6-fold at 500 μM.188 In a noteworthy study based on their structural investigations of α-galactosidase A, Ortiz Mellet, Garcia Fernandez, and collaborators recently attempted optimization of the parent DGJ structure by increasing its lipophilicity introducing interesting thiourea derivatives.154 Indeed, these workers found additional contacts in the active site of the wild-type enzyme (PDB 3GXT) correlating to improved chaperone activities at an optimal concentration as low as 30 μM when compared to the parent compound. In particular, inhibitor 44 (Ki 0.074 μM) led to a more than 7-fold increase of enzymatic activity in the Q279E mutant, which is about 3-fold the activity of DGJ at its optimal concentration of 20 μM. This beneficial activity could also be demonstrated with 301Q affected cells. Contrasting these results, more rigid bicyclic system 45 was only a poor inhibitor and essentially devoid of chaperone activity. Bearing in mind that pharmacological chaperones for lysosomal disorders should be powerful inhibitors at neutral pH in the ER, but should easily dissociate from the enzyme upon successful arrival of the complex in the lysosome, a powerful and elegant new concept was introduced by the same groups189: Chain extension of the wellestablished thiourea moiety of their powerful DGJ derivatives, introducing an acid-labile mixed orthoester featuring one lipophilic medium chain length alkyl substituent provided an efficient chaperone 46 that increased α-galactosidase A activities of mutants R301G and Q279E by 3.5-fold at 20 μM. Furthermore, orthoester cleavage at lysosomal pH value resulted in a noninhibitory truncated compound as could be shown at even 10 times higher chaperone concentration. Clearly, this concept will be of broad applicability and high value for the design of novel nontoxic chaperones for several glycosidase mutation-related lysosomal storage disorders.

2.4 Arylsulfatase A Arylsulfatase A (ARSA, cerebrosyl sulfatase, EC 3.1.6.8) cleaves the 3-sulfate at the galactosyl moiety of sulfatide 47 (Fig. 14) before the final cleavage of β-galactosyl ceramide into its subunits. The ARSA gene is located on chromosome 22 (22q13.33)190,191 and encodes for a 507 amino acid precursor. Mature arylsulfatase A is a 51.1 kDa protein with 489 amino acids and three glycosylation sites, Asp 158, 184, and 350,192,193 forming an octamer at lysosomal pH value. An interesting and unusual structural feature is a formylglycine residue in the hydrate form at position 69 which

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Arnold E. St€ utz and Tanja M. Wrodnigg

O HN O

O

HO OH HO

OH OSO3H 47

Fig. 14 Sulfatide 47.

in concert with an octahedrally coordinated Mg2+ is required for enzymatic activity.194 Crystal structures of human ARSA are available: The first such structure (PDB 1AUK) was reported by von Figura, Saenger, and collaborators and shows a homooctamer composed of a tetramer of dimers.195 Subsequently, the structures of mutants at crucial position 69 in complex with 4-nitrocatechol sulfate, C69A (PDB 1E2S), and C69S (PDB 1E3C), as well as the free C69S mutant (1E1Z) were provided.196 Furthermore, structures of the P426L mutant (1E33)197 and of human enzyme in complex with covalently bound 4-methylumbelliferyl phosphate (1N2K) as well as with O-phospho-tyrosine (1N2L) have been reported.198 Recombinant enzyme from various cell lines has been compared.199 Malfunction/lack of lysosomal arylsulfatase A caused by mutations on the ARSA gene is associated with progressive demyelination of the central and peripheral nervous system by secondary effects of cerebroside-3-sulfate (sulfatide) deposition leading to the lysosomal disease metachromatic leukodystrophy (OMIM# 250100).200,201 Its incidence is ranging between 1:40,000 and 1:150,000 newborns.202–204 Despite indications of enzyme–carbohydrate interactions as judged from crystallographic data, neither potential sugar-mimetic pharmacological chaperones nor inhibitors have been reported, for this enzyme, as yet.

2.5 Lysosomal β-D-Galactocerebrosidase β-Galactocerebrosidase (GalC, EC 3.2.1.46; GH 59), a retaining 77 kDa β-galactosidase, is the last carbohydrate-processing enzyme in the lysosomal degradation sequence of gangliosides and globosides en route to free ceramide. It cleaves the glycosidic bond between the ultimate galactosyl unit and the ceramide aglycon. The GALC gene is located on chromosome

Carbohydrate-Processing Enzymes of the Lysosome

247

14 at position 31 (14q31) and encodes for 669 amino acids with six potential N-glycosylation sites.205 The precursor is transported to the lysosomes where maturation results in two fragments (50 and 30 kDa, respectively).206 Recombinant human galactosylceramidase from CHO cells has been reported.206 The structure of the human enzyme has not been determined, as yet, but the crystal structure of GalC from mouse which shows 83% homology has been reported (apo form: PDB 3ZR5; in complex with D-galactose: 3ZR6).207 Subsequently, the complexes with 4-nitrophenyl β-Dgalactopyranoside (4CCC), with the covalent product of D-galactal addition to active site Glu 258 (4CCD), as well as the enzyme product complex with 208 D-galactose, were published. Furthermore, a range of inhibitorcoordinated structures have been made available (see below). Mutations in the GALC gene lead to globoid cell leukodystrophy also known as Krabbe disease (OMIM# 245200).209 This disorder results in demyelination by accumulation of the cytotoxic metabolite psychosine causing various neurological effects that are finally fatal.210 Rapidly progressing symptoms develop during the first six months of life with loss of vision and severe motor deterioration. Those so afflicted frequently die before the age of 24 months. Attenuated juvenile and adult forms may show variable phenotypes.211 Its incidence is estimated at about 1 in 170,000 births212 in the main parts of Europe, but may become as high as 1 in 170 live births in genetically homogeneous communities as was found in particular Druze and Arab populations.213 Currently more than 150 mutations in the GALC gene are known, but not all of them lead to disease symptoms. Initially, relatively simple organic compounds have been probed as pharmacological chaperones: The D528N mutant was found to induce hyperglycosylation and, consequentially, misfolding. Interestingly, the protein could be stabilized at reduced temperature (30°C) and the piperidine derivative lobeline (48, Fig. 15), a weak inhibitor (IC50: 200 μM) of GALC, was discovered to increase the enzyme activity by more than 50% at 240 μM.214 Achiral 7,30 ,40 -trihydroxyisoflavone (49) effected a 6-fold increase of enzymatic activity in the p.G553R mutant at 200 μM (lobeline; 2-fold at 50 μM), and both compounds led to a 3- to 4-fold increase with the p. E130K + p.N295T mutant at 50–100 μM, whereas neither the p.D187V + p.G323R nor the p.G286D + p.P318R mutants were susceptible to these chaperones.215

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OH OH OH

O HO

O

N CH3 O

48

49

Fig. 15 Noncarbohydrate β-D-galactocerebrosidase inhibitors 48 and 49.

H N

H N HO

HO OH

H N

R HO

HO

OH

NH HO

HO OH

OH

50

H N

OH

51: R = C3H7 52: R = C9H19

H N

O

HO

53

H N HO

HO OH OH 54

OH OH 55

HO

OH

56

Fig. 16 β-D-Galactocerebrosidase inhibitors 50–56.

First insight into imino sugars as inhibitors, and thus potential pharmacological chaperones for Krabbe disease, was provided by Martin and collaborators.216 These workers compared a series of 16 imino sugars concerning their activities and selectivities for GALC, human lysosomal β-galactosidase as well as human α-galactosidase. Highest activities for GALC were observed with 4-epi-isofagomine (18) and the corresponding 5-C-hydroxy derivative 50 (Fig. 16), whereas DGJ derivatives bearing chain extensions at C-1 such as compounds 51 and 52 were found most effective for the α-galactosidase probed with hardly any activity toward the

Carbohydrate-Processing Enzymes of the Lysosome

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Krabbe-related β-galactocerebrosidase. This finding was underscored in a notable contribution by Deane and collaborators who probed the activities of typical β-galactosidase competitively inhibiting imino sugars and, gratifyingly, determined the structures of 4-epi-isofagomine (18) (Ki 0.380 μM, PDB 4UFH), 1-aza-4-epi-isofagomine (53) (0.63 μM, 4UFI), 4-epiisofagomine δ-lactam (54) (52 μM, 4UFJ), DGJ (6) (190 μM, 4UFM), 4-epi-isofagomine-related bicyclic noeurostegine derivative 55 (2300 μM, 4UFL), and pyrrolidine-type 1,4-dideoxy-1,4-imino-D-lyxitol 56 (130 μM, 4UFK) in complex with GALC.217 Not surprisingly, among the collection of compounds probed, 4-epi-isofagomine was found the most potent inhibitor and stabilizer of the protein. The carbasugar N-octyl-4-epiβ-valienamine (NOEV, 5), a potent inhibitor of galactocerebrosidase (IC50 ¼ 0.089 μM at pH 4.2), was examined with human skin fibroblasts featuring late-onset mutations of GALC such as G270D, which responded to this chaperone with increases of residual activities between 16% and 44%.218 Results of more in-depth investigations into the properties of 4-epiisofagomine (18), NOEV (5), and related potentially suitable compounds as pharmacological chaperones for Krabbe disease mutants in suitable cell lines will be most exciting.

3. LYSOSOMAL GLYCOGEN DEGRADATION AND GLYCOGEN STORAGE DISEASE 3.1 Lysosomal α-D-Glucosidase Lysosomal α-glucosidase (GAA, acid maltase, EC 3.2.1.20, GH 31) is responsible for the lysosomal degradation of lysosomal deposits of glycogen to glucose. The GAA gene is located on chromosome 17 (17q25.3) and was characterized in 1990.219 The corresponding 110 kDa protein consists of 952 amino acids and 7 glycosylation sites.220 One of them, Asn 233, is essential for the formation of the mature 76 kDa protein. In 1991, the catalytic site was characterized.221 The first structures (PDB codes 1XSI, 1XSJ, 1XSK) of a GH 31 α-glucosidase, YieI from Escherichia coli, were reported by Strynadka, Withers, and coworkers in 2005.222 Human intestinal maltase-glucoamylase, MGAM, (2QLY), a GH 31 hydrolase that shares 45% sequence identity with GAA,223 as well as complexes with inhibitors (3QMJ, 3L4T, 3L4U, 3L4V, 3L4W, 3L4Z), are also available.224,225 The structure of human lysosomal α-glucosidase has not been reported, as yet.

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Mutations in the acid α-glucosidase gene (GAA gene) lead to deficiency in lysosomal α-glucosidase, characterized by progressive storage of glycogen in the lysosomes. This storage disorder is called Pompe disease (glycogen storage disease type II, acid maltase deficiency; OMIM #232300) after the Dutch pathologist J. C. Pompe.226 The connection of the disease to the lack of acid α-glucosidase was first reported by Hers in 1963.3 Pompe disease is found in all ethnic groups with a prevalence of 1:40,000 to 1:150,000 births with recent studies showing higher numbers of cases in Taiwan (1:20,000) and Austria (1:9000). There are more than 300 pathogenic mutations recorded to date. The phenotype ranges from “floppy babies” with cardiomegaly and life expectancies of less than one year to lateonset cases with first symptoms emerging at age 60 or later. First investigations into ERT were conducted in 1973,227 and ERT with alglucosidase alfa has been available since 2006. Similar to acid α-galactosidase, the development of potential pharmacological chaperones has been retarded by the early and overpowering results with 1-deoxynojirimycin. In 2006, Brooks and coworkers reported that D-glucose, when added to the medium at a level of 6 g/L, increased the production of acid α-glucosidase in CHO-K1 expression cells and stabilized the enzyme activity. In fibroblasts from adult-onset Fabry patients, glucose increased the level of residual enzyme activity.228 At 10 mM, similar effects were observed for the allosteric chaperone N-acetylcysteine (57, Fig. 17).229 Okumiya and collaborators probed DNJ (1) as well as four N-alkyl derivatives for their suitability as pharmacological chaperones for acid α-glactosidase.230 The N-butyl derivative 2 was found to be the most promising, enhancing the lysosomal activity of two (Y455F, P545L) of the four mutants probed (525del/R600C; D645E/R854X) by 14- (Y455F) and 7.9-fold, respectively, at 10 μM. After removal of the chaperone, the activities decreased

SH O

O O H3C

N H

N H

O

OH H N

N

O H N

B OH

O

N H O

O

OH N 57

58

O N H

59

Fig. 17 Noncarbohydrate activators of lysosomal α-D-glucosidase, 57–59.

Carbohydrate-Processing Enzymes of the Lysosome

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with t1/2 2 and 4 days, respectively. It was concluded that the compound would be suitable in terms of efficacy as well as side effects such as typical weight loss, diarrhea, and lymphoid organ shrinkage. Other workers found DNJ and its N-butyl derivative 2 active for L552P and G549R with best effects (1.3–7.5-fold increases) between 10 and 80 μM.231 Additionally, it was found that compound 2 improved the efficacy of ERT.232 For further identification and evaluation of additional DNJ-susceptible mutants, 76 mutations were probed, of which 16 showed increased activity (3- to 20-fold) after treatment of COS-7 cell expressed mutants with DNJ for two days.233 Comparison of DNJ and proteasome inhibitors bortezomib (58) and MG132 (59) revealed impressive effects of up to 4-fold activity increase by the latter two with Pompe mutant c.546G>T at concentrations as low as 10 nM.234 Autophagy and ER stress associated with this particular mutant were ameliorated upon cultivation of fibroblasts in the presence of 20 μM N-butyl-DNJ (2).235 In the course of the drug development for DNJ (1, AT2220), a mouse model was employed for advanced studies concerning delivery and metabolism of the mutant as well as the recombinant human α-glucosidase with concomitant glycogen reduction.236,237 In a study enrolling 13 patients (3 infantile-onset, 10 late-onset), the combination of ERT with administration of N-butyl-DNJ (2) enhanced blood α-glucosidase activity and was found beneficial for 11 individuals and superior to ERT alone.238 Contrasting chaperone-mediated therapy, the glucosidase inhibitor was administered only at the time of the enzyme infusion. A wide range of other potent α-glucosidase inhibitors are available. Selectivity was found, for example, by complementary inhibition in GH 31 and GH 37 families. Further investigations will be necessary in search for selectivity among human GH 31 glucosidases.239 Dose dependency of chaperoning activity may also be exploited to open and widen the therapeutic windows of suitable compounds.

4. ENZYMES OF THE GLYCOPROTEIN DEGRADATION PATHWAY AND GLYCOPROTEINOSES See Scheme 2.

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: Man : GlcNAc Asn : Gal : Neu5NAc

Proteases

: Fuc

Asn

α-L-Fucosidase

Asn

Asn

Aspartyl-N-acetyl-D-glucosaminidase

Endo-N-Acetyl-β-D-glucosaminidase

Neuraminidase I

β-D-Galactosidase

N-Acetyl-β-D-hexosaminidase

β-D-Mannosidase

α-D-Mannosidase

Scheme 2 N-Glycoprotein degradation pathway. Modified from Varki et al.77

Carbohydrate-Processing Enzymes of the Lysosome

253

4.1 Lysosomal α-L-Fucosidase Lysosomal α-L-fucosidase (EC 3.2.1.52) is a retaining GH 29 exoglycosidase and member of subfamily A regarding relaxed substrate tolerance as well as structural features.240 With a pH optimum of around 4.5, it removes the α-L-fucosyl moiety from the core of the asparagine-connected bi-antennary oligosaccharide that arises from excision by exo- and endopeptidases from a degradation-bound glycoprotein.241 The FUCA1 gene is located on chromosome 1 (1p34), and the mature protein consists of 439 amino acids.242,243 Around 30 mutations of this gene are known to date resulting in the storage of fucosylated glycoconjugates of N- and O-glycoproteins in the liver and high concentrations of oligosaccharides and glyco-asparagines in the urine of fucosidosis (OMIM# 230000) patients.244,245 For this rare disease, only around hundred cases have been reported to date with clustered incidence in Italy, Cuba, and the southwest of the United States.246 Pharmacological chaperones for fucosidosis have not been proposed, to date. In the protein data bank, a good selection of α-L-fucosidase crystal structures are available, but these are nearly exclusively of procaryont origin with only limited homologies to the human lysosomal enzyme: The structure of the enzyme from Thermotoga maritima, which shares 34% identity with the human fucosidase, was reported in 2004.247 PDB entries 1HL8, 1HL9, and 1ODU show the free enzyme and its complexes with 2-deoxy-2-fluoro-L-fucose and with L-fucose, respectively. Furthermore, structures of the free enzyme and a collection of nine enzyme–inhibitor complexes with powerful α-L-fucosidase inhibitors 60–68 (Fig. 18), structurally based on 1,5-dideoxy-1,5-imino-L-fucitol (69) are available (PDB entries 2ZWY, 2ZWZ, 2ZX5–2ZX9, 2ZXA, 2ZXB, 2ZXD).248 Structures of the GH 29 α-L-fucosidase from Bacteroides thetaiotaomicron (2WVV) that has 27% homology to the human enzymes, its complex with 4-nitrophenyl α-L-fucopyranoside (2WVU), the structure with covalently bound 2-deoxy-2-fluoro-α-L-fucopyranosyl residue in the active site (2WVS) and with inhibitor 70 (2WVT; Fig. 19), as well as enzyme– inhibitor complexes with compound 71, with parent compound 69 as well as with furanoid inhibitors 72 (4J28), 73 (4JL2), a trimeric scaffold with the same ligand (4JL1) and with rigid iminosugar systems 74–76 (4PCS, 4PCT, 4PEE), were reported by Davies in collaboration with various groups.249–253 Furthermore, complexes with dimeric (5I5R) pyrrolidine-type inhibitors and ferrocene-substituted inhibitors (5HDR) have recently been deposited

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Arnold E. St€ utz and Tanja M. Wrodnigg

O H N

H3C

N H

NH2

HO

HO

OH

OH

60

61

NH

OH 62

OH

O

H N

H3C

N H

HO

OH

O H N

H N

N H

HO

O H3C

H N

H3C

OH

OH

NH

O

H N

H3C

O N H

HO

OH

OH 63

H N

H3C

N H

HO

OH

OH

OH

64

65

O H N

H3C

H N

H N N H

HO

OH

HO

OH

H N

H3C

CH3 HO

OH

HO

OH

OH

OH

OH

OH

66

67

68

69

Fig. 18 α-L-Fucosidase inhibitors 60–69.

O O H N

H N

HO

OH HO

N H

OH

HO

OH

OH

OH

70

71 N O

HN H3C

H N

H3C

N

HO

OH

R

H N NHBn

HO

72

H N

H3C

OH

H3C

HO

73

OH

74: R = Ph 75: R = H

O

N

N

H N

HO

OH 76

O

N

N

H3C

H3C

HO

OH

HO

OH

OH

OH

77

78

Fig. 19 Reversible (70–76) and irreversible (77 and 78) inhibitors of α-L-fucosidases.

in the data bank. 5a-Carba-fucosylamid-2-yl residues covalently bound to the Bacteroides α-fucosidase (4WSJ, 4WSK) resulted from carba sugar 1,5a-aziridines 77 and 78 being investigated as activity-based proteinprofiling tools.254

Carbohydrate-Processing Enzymes of the Lysosome

255

Several additional structures of GH 95 enzymes as well as GH 29 subfamily B fucosidases may also be found in the database. GH 29 α-L-fucosidases have recently been split into subfamilies A and B based on their individual substrate requirements with subfamily A containing enzymes with broader selectivity that also hydrolyze 4-nitrobenzyl α-L-fucopyranoside and subfamily B, the members of which are characterized by their specificity for α-(1 ! 3/4)-fucosidic linkages and no activity toward the synthetic fucoside.255,256 Moreover, structures of the human or other mammalian enzymes have not been available to date, but would be “sorely needed”256 for in-depth mechanistic understanding and the design of inhibitors that may be able to distinguish between GH 95 and GH 29 enzymes, and, furthermore, may be selective for one of the two GH 29 subfamilies. Nonetheless, an inhibitor-based comparison has been made for the Thermotoga and the human enzyme based on their susceptibilities toward a set of fucose-resembling inhibitors that featured a range of functionalities already indicated.257 Differences between these fucosidases were discussed. In a recent guiding reference, a “hydrophobic ridge”253 at the aglycon-binding site of GH29A fucosidases was proposed and investigated with suitably designed inhibitors featuring a lipophilic substituent interacting with this region of the +1 site. This may suggest the screening of related amphiphilic inhibitors for selectivity with subfamily A enzymes, in particular with the human lysosomal α-fucosidase. Despite the broad interest in fucosidases and opposed to other biological targets where fucosidases are also involved, the topic “fucosidosis” has remained in the second row of research activities, thus far. In particular, chaperone-mediated therapy has not been suggested as a potential treatment for fucosidosis, as yet. On the other hand, based on the impressive collection of various types of pyranoid as well as furanoid α-L-fucosidase inhibitors known to date with examples mentioned above but explored in different context,248,252,258–260 lead compounds for the activation of structurally compromised lysosomal α-L-fucosidase mutants may already be at hand and awaiting investigations.

4.2 Neuraminidase 1 In humans, four different sialidases (NEU1–NEU4), classified by their intracellular locations and different substrate specificities as well as physiological functions, are known.261 Neuraminidase 1 (lysosomal neuraminidase, lysosomal sialidase, NEU1, EC 3.2.1.18, GH 33, 45.5 kDa), one of these

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Arnold E. St€ utz and Tanja M. Wrodnigg

isoenzymes that are also involved in a variety of signaling pathways and pathological processes, is an exo-glycosidase with a pH optimum of pH 4.6 cleaving α-2,3-, α-2,6-, and α-2,8-glycosidic bonds.262 The corresponding NEU1 gene is located on chromosome 6 (6p21.3) and encodes for a 415amino acid precursor which becomes a 48.3 kDa mature active enzyme by glycosylation and cleavage of a 47-amino acid N-terminal signal peptide.263 Mutations in the NEU1 gene may cause dysfunctional protein and, consequently, accumulation of sialylated oligosaccharides in tissues and urine leading to the lysosomal disease, sialidosis (OMIM# 256550).263,264 The infantile-onset form is characterized by skeletal dysplasia, mental retardation, and hepatosplenomegaly. Estimations on its incidence differ considerably between 1:2,000,00044 and 1:1,000,000 in the general population. Recent anecdotal evidence indicates that NEU1 mutants may be susceptible to pharmacological chaperones such as the steroid celastrol (79, Fig. 20) in combination with tripeptide analog MG132 59 or the effects of thymoquinone (80) on NEU4 sialidase.265,266 The latter enzyme was also discovered to be expressed on the surface of fibroblast cells from sialidosis type I patients. Closer to carbohydrate mimetics, C-9-modified derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA, 81, Fig. 21) as selective inhibitors of NEU1 were reported by Magesh, Kiso, and coworkers.267 Their compounds, in particular the ones featuring simple N-alkyl substituents such as 82, 83, and 84, exhibited IC50 values in the low μM range with practically no inhibitory effect on NEU2–NEU4.

O OH

O

H O O HO 79

Fig. 20 Modulators of neuraminidase activities, 79 and 80.

80

257

Carbohydrate-Processing Enzymes of the Lysosome

OH

O

O

OH

H

O H O

O HO

OH

H3C

R

N H

OH HN

OH

H3C

OH HN

OH

OH

O

O 82: R = CH3 83: R = C3H8 84: R = C4H10

81

Fig. 21 Neuraminidase inhibitors 81–84.

O OH

HN N

HO OH

O

NH2

O

O

H O

NH2

HN

OH

H N

O O

O

H N

H3C

H2 N

85

OH HO OH

86

O

87

Fig. 22 Neuraminidase inhibitors 85–87.

Numerous other carbohydrate or carba sugar-based sialidase inhibitors such as Relenza® (85, Fig. 22) or Tamiflu® 86, and related compounds are commercially available and may provide additional leads toward selective activation of sialidosis-related human NEU1 mutants. In the realm of imino sugars, siastatins,268,269 in particular siastatin B (87), may offer clues concerning potential carbohydrate-derived pharmacological chaperones for susceptible sialidosis mutants.

4.3 N-Acetyl-α-D-galactosaminidase N-Acetyl-α-D-galactosaminidase (α-NAGA, EC 3.2.1.49, GH 27) is a retaining exoglycosidase with pH optimum 4.6 removing α-connected N-acetylgalactosamine residues from various oligosaccharides, including blood group A glycans and O-linked glycoproteins. It consists of a homodimer with each monomer containing 394 residues. In mature wild-type protein, five of the six potential glycosylation sites are occupied.270 Several crystal structures of the enzyme at good resolutions are available: In 2002, ˚ structure of chicken α-NAGA (PDB 1KTB) and its complex the 1.9 A (1KTC) with N-acetyl-D-galactosamine were reported.271 Structures of

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Arnold E. St€ utz and Tanja M. Wrodnigg

O2N H N

NO2 H N

O

HO

HO F HO

NO2

F

HO

NHAc

OH

OH

88

89

Fig. 23 N-Acetyl-α-D-galactosaminidase inhibitors 88 and 89.

the human enzyme apo form (PDB 3H53) and its complexes with N-acetyl-D-galactosamine (3H54), with D-galactose (3H55), as well as with a 2-deoxy-2,2-difluoro-D-“galactosyl” residue (introduced by employing 20 ,40 ,60 -trinitrophenyl 2-deoxy-2,2-difluoro-D-lyxo-hexopyranoside (88, Fig. 23))272,273 covalently bound in the active site (PDB 3IGU) were subsequently published.274 In addition, the structures of complexes with 2-N-acetyl-2,5-diamino-1,2,5-trideoxy-1,5-imino-D-galactitol (DGJNAc, 89, PDB 4DO4, Ki 41 nM), DGJ (6, Ki 1.48 μM, 4DO5), and D-glucose-soaked enzyme (4DO6) are available.275 Mutations on the NAGA gene at chromosome 22 (22q13.2) lead to loss of enzymatic activity in the lysosome and accumulation of substrates causing Schindler/Kanzaki disease which was first described in 1987.276 Its incidence is estimated to be less than 1:1,000,000.277 The applicability of chaperone-mediated therapy to Schindler/Kanzaki was demonstrated in a guiding reference275 by Fleet and coworkers who proposed imino sugars DGJ (6) and, in particular, its 2-acetamido-2-deoxy analog 89 as lead compounds. The first synthesis of the latter was reported in 1990 but had the disadvantage to rely on DNJ (1), a (at that time) not readily available compound, as the starting material.278 A state-of-the-art approach from D-glucofuranurono-6,3-lactone was recently provided by the same group.131,279 These workers could demonstrate an, albeit small, beneficial effect of DGJ (0.5 mM) as well as of compound 89 (0.1 mM) in case of the S160C mutant. In contrast, an R329W cell line did not respond to either of these potential chaperones.275

4.4 Lysosomal α-D-Mannosidase Lysosomal α-mannosidase (LAMAN, EC 3.3.1.24, GH 38), a retaining enzyme,280 is encoded by the MAN2B1 gene, located on chromosome

259

Carbohydrate-Processing Enzymes of the Lysosome

19 (at 19p13.2). The native enzyme is a dimer with a molecular mass of 250 kDa and works best at pH 4.0–4.5. It features eight possible glycosylation sites, of which seven are glycosylated.281,282 A crystal structure of the ˚ resolution was reported in bovine kidney enzyme (PDB 1O7D) at 2.7 A 283 2003. LAMAN hydrolyzes α-1,2-, α-1,3-, and α-1,6-mannosides during the degradation of N-linked oligosaccharides. Mutations lead to the accumulation of mannose-containing oligosaccharides in the lysosomes with formation of large vacuoles around the storage material causing the autosomal recessive glycoprotein degradation disorder α-mannosidosis (OMIM# 248500). More than 40 such mutations are known to date.284 Patients suffering from α-mannosidosis accumulate oligomannosidic structures in urine and tissues.241,285,286 As early as 1983, the natural indolizidine alkaloid swainsonine (90, Fig. 24), a potent α-mannosidase inhibitor,287 has been reported to increase levels of lysosomal α-mannosidase in rat liver as well as in rat brain by 3.5and 2.4-fold, respectively.288 In addition, several plasma acid hydrolase activities were also found upregulated. This effect reversed upon withdrawal of the inhibitor. Monocyclic analogs—in a wide sense—of swainsonine, 1,4-dideoxy-1,4-imino-D-mannitol derivatives 91 and 92, were also discovered to inhibit lysosomal α-mannosidase, although by a factor of 20 less efficiently than swainsonine.289 Rose and coworkers examined the inhibitory effects of five-membered aminocyclitol mannostatine A (93, Fig. 25), swainsonine as well as three 5-N-benzyl-substituted derivatives (94–96) of 5-amino-1,4,5-trideoxy1,4-imino-D-ribitol with both mannostatine and swainsonine (Ki ¼ 0.4 μM, each), the most powerful inhibitors in this study.290 The L-enantiomer of 1,5-dideoxy-1,5-imino-allitol (97, Fig. 26) showed IC50 ¼ 64 μM, whereas DMJ (1,5-dideoxy-1,5-imino-D-mannitol (98)) was found devoid of activity with the lysosomal mannosidase,291

OH

OH N HO

H N

F

H N H3C

H HO

OH

HO

90

Fig. 24 D-Mannosidase inhibitors 90–92.

OH 91

HO

OH 92

260

Arnold E. St€ utz and Tanja M. Wrodnigg

S H2N

CH3

R H N

HO

OH

N

HO

HO

HO

OH

O

N H

N H

93

HO

OH 94

OH

95: R = H 96: R = CH3

Fig. 25 D-Mannosidase inhibitors 93–96.

H N

H N

HO

HO HO

OH

HO

OH

OH

OH

97

98

Fig. 26 D-Mannosidase inhibitors 97 and 98.

pointing to a certain preference for the manno motif on furanoid scaffolds by the enzyme. Interpretation of these, albeit isolated, results may allow for speculations as to the applicability of configurationally suitable and selective glycosidase inhibitors as potential pharmacological chaperones for some of the glycoprotein degradation disorders mentioned.

4.5 Lysosomal β-D-Mannosidase Lysosomal β-mannosidase (EC 3.2.1.25, MANBA), a retaining GH 2 representative, cleaves the β-mannosidic bond of the disaccharide β-Dmannosyl-(1 ! 4)-2-acetamido-2-deoxy-D-glucose as is present in all N-glycoproteins. The corresponding gene is located on chromosome 4 (4q22–q25). Crystal structures of two GH2 β-mannosidases, from B. thetaiotaomicron (PDB code 2JE8)292 as well as from Trichoderma harzianum (4CVU, 4UOJ),293 have been reported. There are less than twenty mutations known thus far leading to the lysosomal storage disease β-mannosidosis (OMIM# 248510). Worldwide,

Carbohydrate-Processing Enzymes of the Lysosome

261

around twenty cases are known, and the statistical incidence was reported to be too difficult to be estimated with mild or nonspecific symptoms never being diagnosed.294 Consequently, research into options for the application of selective β-D-mannosidase/mannosyl transferase inhibitors as potential agents for substrate reduction or chaperone-mediated therapy has not being deemed worthwhile, as yet.

4.6 Aspartyl-N-acetyl-D-glucosaminidase The amidase aspartyl-N-acetyl-D-glucosaminidase (AGA, EC 3.5.1.26) cleaves the bond between asparagine and N-acetyl-D-glucosamine (GlcNAc) as one of the final steps of glycoprotein degradation in the lysosomes. The AGA gene is located at chromosome 4 (4q32–q33). The tetrameric enzyme (88 kDa) consists of two α- and two β-units. Crystal structures of the free human enzyme (PDB 1APY) as well as of its complex ( 1APZ) with the product at 2 and 2.3 A˚, respectively, have been reported.295 Furthermore, a structure of the T152C precursor protein (3LJQ) is available.296 More than 30 mutations that reduce the enzyme’s activity to 10% of the wild type or less causing the glycoproteinose aspartylglucosaminuria (OMIM# 208400) are known. The incidence of this disorder is estimated at 1:2,000,000 live births in Australia, 1:600,000 to 1:800,000 in most of Europe, but may be as high as 1:18,000 in other regions, particularly in Finland.203,297 The three-dimensional positions of a range of mutations causing aspartylglucosaminuria were mapped, and their structural effects were discussed by Sakuraba and coworkers.298 Inhibition studies employing a series of amino acids and other simple organic compounds, including a selection of aspartic acid analogs, provided a few inhibitors such as N-acetylcysteine and 3-hydroxybutanone with Ki values in the single-figure millimolar range.12,299 Investigations into the significance of the glycon part for enzyme inhibition and potential activation of AGA mutants in chaperone-mediated therapy have not been reported thus far.

5. ENZYMES INVOLVED IN MUCOPOLYSACCHARIDE DEGRADATION AND MUCOPOLYSACCHARIDOSES See Schemes 3 and 4.

2S

2S α4

α4

6S β4

: GlcNAc

α3

NS S Iduronic acid-2-sulfatase 2S α4

α4

4S α3

4S β4

β3 α-L-Iduronidase

: GalNAc

6S β4

4S

α4

4S β4

NS

β3

S Heparan-N-sulfatase 2S α4

6S β4

S β4

S N-Acetyl-β-Dhexosaminidase A or B

α4

6S α4

N-Acetylglucosamine-4-sulfatase

4S β4

β3

Heparin Acetyl-CoA:α-D-glucosaminideN-acetyltransferase

N-Acetyl-β-D-hexosaminidase A or B 4S

α4

β3 N-Acetyl-α-D-glucosaminidase

6S β4

Iduronic acid-2-sulfatase

: Glucosamine GlcN α-L-Iduronidase

α4

β3 S

: Iduronic acid IdoA α4

NS 2S

4S β4

: Glucuronic acid GlcA

6S β4

4S

2S α4

4S

β-D-Glucuronidase 4S

α4

β-D-Glucuronidase

S

N-Acetyl-α-D-glucosaminide-4-sulfatase

6S α4 S

N-Acetylglucosamine-6-sulfatase

α4 N-Acetyl-α-D-glucosaminidase

Scheme 3 Heparan sulfate (left) and dermatan sulfate (right) degradation pathways. Modified from Varki et al.77

6S

6S

β4 β3

6S β4

β-

: GlcNAc

S

: Gal 6S β4

β-D-Galactose-6-sulfatase

Hyaluronan

6S β3

β4

β-

Hyaluronidase β-D-Galactosidase

6S

β4

β4

β-D-Glucuronidase

β-

S N-Acetyl-D-galactosamine-6-sulfatase

β4

β3 N-Acetyl-β-D-hexosaminidase

6S β3

β4

: Glucuronic acid GlcA

β3

6S β3

N-Acetyl-β-Dhexosaminidase A or B

β3

β-

β3 N-Acetyl-β-D-galactosaminidase

β-D-Glururonidase

6S β4

β-

6S

β-D-Galactosidase 6S β-

S

: GlcNAc

N-Acetylglucosamine-6-sulfatase

β-

Scheme 4 Keratan sulfate (left) and hyaluronan (right) degradation pathways. Modified from Varki et al.77

264

Arnold E. St€ utz and Tanja M. Wrodnigg

5.1 Lysosomal α-L-Iduronidase Lysosomal α-L-iduronidase (glycosaminoglycan α-L-iduronohydrolase, EC 3.2.1.76, GH 39, retaining) is a vital enzyme present in the lysosomes of all cells which catalyzes the degradation of dermatan sulfate and heparan sulfate.300,301 The IDUA gene is located on chromosome 4 (4p16.3). The corresponding native protein has 653 amino acid residues and is then N-glycosylated at six sites leading, after removal of 26 residues from the N-terminal, to the mature enzyme.302–305 The catalytic mechanism involving anchimeric assistance by the substrate’s uronic acid moiety was reported by Withers and coworkers.306 Crystal structures of the human enzyme are available in two space groups (PDB codes 4OBS, 4MJ2, 4MJ4, 3W81).305,307,308 Furthermore, structures of its complexes with iduronic acid (3W82, 4OBR),305,307 with 5-fluoro-α307 L-idopyranosyluronic acid fluoride 99 (4KGJ, Fig. 27), with covalently bound 2-deoxy-2-fluoro-α-L-idopyranuronyl residue in the active site (4KH2)307 as well as with the inhibitor 1,5-dideoxy-1,5-imino-L-idopyranuronic acid (100, 4KGL).307 have been reported. The locations of 33 mutations have been mapped,302 and molecular modeling approaches toward functional analysis of selected mutations on the protein have been conducted.309,310 Mutations producing catalytically compromised or incompetent α-Liduronidase lead to the accumulation of dermatan sulfate and heparin sulfate, as well as corresponding oligosaccharides with a high level of urinary glycosaminoglycans. These are usually the preliminary indication of the lysosomal storage diseases: Hurler (MPS IH, OMIM# 607014), Hurler/Scheie (MPS IH/S, OMIM# 607015), and Scheie (MPS IS, OMIM# 607016).311 Hurler represents the most severe form of MPS I, Hurler/Scheie describes an intermediary level of severity, and Scheie is the mildest form of the disease. More than 100 such mutations are known thus far.312,313 With a combined prevalence of 1 in 100,000 live births314 and highly variable presentation, diagnosis may remain difficult. For treatment, ERT has been approved, while O HO2C

O

H N

F

CO2H

HO

F

CO2H O

O

HO

HO

OH OH 99

HO

O

HO

O

OH OH 100

Fig. 27 α-L-Iduronidase inhibitors 99–102.

HO

OH 101

HO

OH 102

265

Carbohydrate-Processing Enzymes of the Lysosome

O

O

HO

O H N

H N HO HO

O H N

HO

OH

OH

O H N

O

O

HO HO

OH

N N

N N

HO HO

OH

HO

OH

OH

OH

OH

OH

OH

103

104

105

106

107

Fig. 28 α-L-Iduronidase inhibitors 103–107.

bone marrow as well as stem-cell transplantation and gene therapy have been investigated. Residual enzyme activity has been correlated with the respective phenotype with Hurler fibroblasts (five mutants probed) exhibiting less than 0.1% up to 0.6%, Hurler/Scheie fibroblasts (three mutants investigated) showing 0.2–0.3%, and Scheie fibroblasts (seven mutations tested) exhibiting 0.3–1.8% of wild-type activity.315 In 1972, Weissmann and Santiago reported, albeit weak, inhibitory activity of D-glucaro-1,4-lactone (101) with lysosomal α-L-iduronidase from rat liver (Ki 690 μM at pH 3.5).316 The corresponding L-idarolactone 102 showed an IC50 value of 40 μM.317 Fellows and collaborators reported the inhibitory activity of 2,6dideoxy-2,6-imino-L-gulonic acid (103, Fig. 28), the glucuronic acid analog of compound 1 (DNJ), a natural product from the African legume Baphia racemosa, against human liver β-D-glucuronidase (IC50 ¼ 80 μM at pH 4.75) as well as against α-L-iduronidase (96% inhibition at 1 mM and pH 3.5) and suggested its application for the induction of mucopolysaccharidosis.318 From a suitably protected derivative of 1, compound 103 and the corresponding deoxy derivative 104 were subsequently prepared by Takahashi and Kuzuhara.319 Syntheses of 5-amino-5-deoxy-D-glucaro- (105) as well as -L-idaro-1,5-lactams (106) were reported by Pabba and Vasella in 2005.320 Compound 106 exhibited Ki 94 μM with human α-L-iduronidase at pH 4.5, whereas the corresponding glycotetrazole 107 was found inactive.321 Schuchman and Desnick observed that the sequential addition of cystamine, MgCl2, and pyridoxal phosphate stimulated residual α-Liduronidase activities up to 35% of normal and suggested “that it may be possible to enhance the residual enzymatic activity in patients with MPS I by further investigation of methods to manipulate the conformation and substrate binding of the mutant enzyme.”13 Recently, aminocyclitol antibiotics, gentamicin C1a-, amikacin-, as well as paromomycin-derived compounds NB54 (108, Fig. 29) and NB84 (109), were reported to enhance residual α-L-iduronidase activity in W392X mice

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Arnold E. St€ utz and Tanja M. Wrodnigg

OH

OH

H N

H2N

H N

H2N

NH2

NH2

OH

O O

O

O

OH

O

HO O HO

NH2

NH2 OH

HO

O

H3C

O

OH O

HO

OH

O NH2

NH2 OH

108

HO

OH

109

Fig. 29 α-L-Iduronidase activity enhancers 108 and 109.

by factors of up to 15.5-fold or up to 0.32% of wild type based on their ability to suppress premature termination codons (in-frame nonsense mutations). Urinary glycosaminoglycans were found reduced by 25% upon treatment with 30 mg/kg of compound 109.322 Similar levels of activity had been found323,324 in patients with milder forms of MPS I hinting toward amelioration of symptoms triggered by the aminoglycoside 109.

5.2 Lysosomal Heparan-N-sulfatase Heparan-N-sulfatase (EC 3.10.1.1) is the only lysosomal sulfatase catalyzing the hydrolysis of N-linked sulfate groups from the nonreducing terminal glucosamine moieties of heparan sulfate and heparin.325 The SGSH gene is located on chromosome 17 (17q25.3) and encodes for a 56-kDa protein containing five potential glycosylation sites. The recombinant native enzyme from CHO cells was found a dimer.326 The enzyme is inhibited by sulfate as well as by phosphate in the single-figure, millimolar range.327 Crystal structures of the enzyme from two different crystal forms are available (PDB codes 4MHX, 4MIV).327 Mutations in the SGSH gene cause the mucopolysaccharidosis Sanfilippo A (MPS IIIA, OMIM# 252900) having an incidence of 1 in 100,000 live births,328,329 thus being the most common of the four Sanfilippo disorders (MPS IIIA–MPS IIID), first reported by Sanfilippo and coworkers in 1963.330 The locations of 80 of the more than 100 known mutations have been mapped, and their effects on the wild-type structure are discussed.327 Gene therapy, enzyme-replacement therapy,331 as well as substrate reduction therapy are in clinical trials or in development. By reduction of glycosaminoglycan biosynthesis affecting chain elongation, rhodamine B (110, Fig. 30) showed beneficial effects in human fibroblasts332 as well as in male MPS IIIA mice.333 The isoflavone-type natural product and tyrosine kinase inhibitor genistein (111) was also found to affect

267

Carbohydrate-Processing Enzymes of the Lysosome

H3C

CH3 Cl

H3C

N

O

N

CH3

HO

O

O

OH

HO R

1

NHAc

R COOH

110

OH

O OH

111

OH

112: R = H, R1 = F 113: R = F, R1 = H

Fig. 30 Active compounds 110–113.

glycosaminoglycan biosynthesis334,335 as do the more specific inhibitors of chain elongation, 4-deoxy-4-fluoro derivatives of 2-acetamido-2deoxy-D-glucose (112) and -D-galactose (113).336 For Sanfilippo A, to the best of our knowledge, CMT has not been investigated, as yet.

5.3 Lysosomal N-Acetyl-α-D-glucosaminidase Lysosomal N-acetyl-α-D-glucosaminidase (NAGLU, EC 3.2.1.50) is a retaining GH 89 enzyme that removes N-acetyl-D-glucosamine from the nonreducing end of heparan sulfate. The corresponding gene is located on chromosome 17 (17q21.2) and encodes for a protein comprising 720 amino acid residues (80.4 kDa) forming a functional homotrimer. Mammalian N-acetyl-α-D-hexosaminidase was isolated and purified from rabbit liver in 1968.337 Purification and properties of the human enzyme were reported in 1977.338 Recombinant human enzyme from CHO cells has become available in 2000,339 based on work by Neufeld and collaborators.340 For the investigation of potent carbohydrate-based inhibitors, the crystal structure of N-acetyl-α-glucosaminidase from Clostridium perfrigens, which shows approximately 30% of amino acid identity, served as a model for the human enzyme (PDB code 2VCC).341 In addition, structures of the GlcNAc complex (2VCA) as well as of the complexes with PUGNAc (114, Fig. 31) (2VCB) and with 2-acetamido-1,2,5-trideoxy-1,5-imino-Dglucitol (31, Fig. 9) (2VC9), the 2-acetamido-2-deoxy derivative of compound (1, Fig. 1), were reported. The crystal structure of human N-acetyl-α-glucosaminidase has recently been deposited (PDB 4XWH). Mutations in the NAGLU gene result in the mucopolysaccharidosis Sanfilippo B (MPS IIIB, OMIM# 252920) as was concluded from the

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O O HO

N O

HO

N H

NHAc OH 114

Fig. 31 PUGNAc (114).

lacking of this enzymatic activity in tissues of patients,342,343 and the residual N-acetyl-α-glucosaminidase activity in patients’ fibroblasts was found to correlate with the severity of the disease.344 Notably, increased levels of lysozyme and deposits of hyperphosphorylated tau protein, the latter also being the case in other tauopathies such as Alzheimer’s disease, were detected in an MPS IIIB mouse model.345 MPS IIIB has a quite varying geographic incidence. For example, southern European countries (0.78:100,000 in Portugal and Greece, 2.6:100,000 in Germans of Turkish descent) are seemingly more affected than France (0.08:100,000), Great Britain (0.36:100,000), or Germany (0.42:100,000) and the Netherlands (0.42:100,000).204,328,329 There are more than 150 mutations related to MPS IIIB reported in the Human Gene Mutation Database (HGMD®),346 including 90 missense mutations. Aiming for the development of potential pharmacological chaperones for the treatment of MPS IIIB, Vocadlo and collaborators investigated typical competitive hexosaminidase inhibitors PUGNAc (114), deoxynojirimycin derivative 31 (Fig. 9), as well as the corresponding acetamidodeoxy derivative of castanospermine (33) with the C. perfrigens enzyme.341 PUGNAc, a potent inhibitor of Hex B (Ki 36 nM) and of O-GlcNAcase (OGA; Ki 46 nM),347 showed a Ki value of 6.2 μM. Iminoalditol 31 exhibited three orders of magnitude stronger inhibition (Ki 3.6 nM), while its bicyclic analog 33 had Ki 90 nM. The human recombinant N-acetyl-αglucosaminidase was considerably less sensitive toward the deoxynojirimycin derivative 31 (Ki 0.45 μM), but gave a practically identical value of 87 nM with castanospermine derivative 33.339 To the best of our knowledge, results of screening with MPS IIIB patients’ cell lines have not been reported for these or other inhibitors, thus far.

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5.4 Heparin Acetyl-CoA:α-D-glucosaminideN-acetyltransferase Heparin acetyl-CoA:α-D-glucosaminide-N-acetyltransferase (EC 2.3.1.78) is a lysosomal transmembrane protein catalyzing acetyl transfer to desulfated 2-NH2 of the nonreducing glucosamine residue in heparin or heparan sulfate for further downstream processing by N-acetyl-α-D-glucosaminidase. The HGSNAT gene is located on chromosome 8 (8p11.2) and encodes for 635 amino acid residues containing protein. The mature enzyme has been shown to be a monomer.348 Characterization of the human enzyme348–351 and the encoding gene352,353 have been performed. Mutations of the enzyme causing deficiency of the catalytically competent protein result in Sanfilippo syndrome type C (MPS IIIC).354,355 To date, more than 50 mutations have been identified.356,357 Interestingly, of 17 mutants screened with the inhibitor D-glucosamine (Ki 280 μM) as a potential pharmacological chaperone, five showed response to this compound. Notably, two of them, R344C and S518F, account for 22% and 29% of the alleles in Dutch patients. R344C has also been found in France, United Kingdom, Germany, and Singapore. Two other responsive mutations are also distributed across Europe.356 This, albeit isolated, finding indicates that suitable glucosamine derivatives or analogs may also be found inhibitors and could be useful as potential pharmacological chaperones for MPS IIIC.

5.5 Lysosomal N-Acetyl-D-glucosamine-6-sulfatase N-Acetylglucosamine-6-sulfatase (EC 3.1.6.14) hydrolyzes 6-sulfate groups in N-acetyl-D-glucosaminide units of heparin sulfate as well as keratan sulfate.358,359 The GNS gene is located on chromosome 12 (12q14.3)360 and encodes for a 552-amino acid protein with 13 potential N-glycosylation sites. The enzymes from bovine kidney,361 as well as from human liver362,363 and human neutrophils,364 have been purified and characterized. Recombinant sulfatase from goat was made available in 1997.365 Crystal structures have not been reported thus far. Mutations in the GNS gene lead to Sanfilippo D disease (MPS IIID, OMIM# 252940). The incidence for this particular disorder is in the range of 1:1,000,000 live births, MPS IIID thus being one of the rarest lysosomal diseases.366–368 The first mutation was identified only in 2003.369 In context with the potential application of carbohydrate analogs for treatment, available pieces of information so far have been confined to introductions in patent applications.

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5.6 Lysosomal N-Acetyl-D-galactosamine-6-sulfatase Lysosomal N-acetylgalactosamine-6-sulfatase (EC 3.1.6.4) cleaves the 6-sulfate of N-acetyl-D-galactosaminyl residues in chondroitin sulfate and keratin sulfate.370 The enzyme from human placenta was purified and characterized in 1979,370 and the one from human liver was reported in 1991.371 The GALNS gene is located on chromosome 16 (16q24.3)372 and encodes a 522-amino acid protein providing a homodimer containing 496 amino acids per subunit after removal of the signal peptide. A recombinant human N-acetylgalactosamine-6-sulfatase from CHO cells was reported in 1995,373 paving the way for ERT.374 Structures of the human enzyme (PDB 4FDI) and of its complex with N-acetyl-D-galactosamine (4FDJ) have been reported.375 Structure 4FDJ shows coordination of the sugar’s ring oxygen by Lys 310 and an H-bond to 6-OH from Gln 311, indicating the involvement of the sugar unit in the binding process. Mutations in the GALNS gene result in mucopolysaccharidosis type IV A (Morquio A, OMIM# 253000).376 This disease shows varying geographic incidence377 (for example, 1:76,000 in Northern Ireland,378 1:640,000 in Western Australia)379 with an estimated average of 1:200,000 live births.380 By 2014, more than 170 mutations have been described, the majority of 75% being missense/nonsense mutations.380,381 Mapping of 120 missense mutations onto the structure has revealed that the majority affect the hydrophobic core, suggesting that MPS IV A is mainly a result of misfolding.375 In combination with molecular docking,381 and the setup of a database,382 a powerful toolset for genotype–phenotype correlation and prediction has thus become available. Inspection of the crystal structure (PDB code 4FDJ) as well as the applicability of nonnatural fluorescent substrates383 may allow for the assumption that a certain percentage of the Morquio A-related mutations would be susceptible to CMT employing suitable C-6-modified GalNAc analogs.

5.7 N-Acetyl-D-galactosamine-4-sulfatase (Arylsulfatase B) N-Acetyl-D-galactosamine-4-sulfatase (arylsulfatase B, EC 3.1.6.12) is required for the hydrolysis of 4-sulfates of the N-acetyl-D-galactosamine4-sulfate units of chondroitin sulfate and dermatan sulfate. In addition, the enzyme exhibits activity with N-acetylglucosamine-4-sulfate as substrate. The ARSB gene is located on chromosome 5 (5q14.1). The crystal structure ˚ was reported in 1997.384 of the human enzyme (PDB 1FSU) at 2.5 A Inherited enzyme deficiency results in the lysosomal storage disease

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Maroteaux–Lamy syndrome385 (MPS VI, OMIM# 253200), which has an incidence of approximately 1:250,000. “Sulfatase B” from ox liver was purified and characterized as early as 1954,386,387 and the enzyme from human liver was reported in 1958.388 Connection between the enzyme and Maroteaux–Lamy syndrome (MPS VI) was noted by several researchers about twenty years later.389–392 Human liver N-acetylgalactosamine-4-sulfatase was purified to homogeneity, and the chromosome assignment was subsequently reported.393,394 In a feline MPS VI model, residual arylsulfatase B activity could be enhanced in the presence of dithiothreitol or cysteamine (11- and 20-fold, respectively) in an early example of “enzyme manipulation therapy.”14 Differences in the maturation of normal and mutant arylsulfatase B were noted by Figura and coworkers.395 Form I consisted of a 47- and 11.5-kDa polypeptide, while form II had 40- and 31-kDa subunits. The cDNAs encoding for enzyme were cloned,396 and recombinant N-acetylgalactosamine-4-sulfatase from CHO cells was employed in human Maroteaux–Lamy fibroblasts for experimental correction. However, it was found that the endocytosed enzyme had a considerably shorter half-life than endogenous human N-acetylgalactosamine4-sulfatase.397 Genotype–phenotype correlations of mutations have been conducted and updated.398–402 Most mutations are unique to a patient or are present in a small group of patients, only. Along with Maroteaux–Lamy disease, abnormal storage of GM2- as well as GM3-gangliosides and the presence of unesterified cholesterol were detected.403 ERT (galsulfase from CHO cells) was approved in 2005 with sales of $2.3 million ($US) in its first quarter on the market.404 Work on potential inhibitors with pharmacological potential has been scarce. Recently, the first set of small molecules inhibiting in the submicromolar range was reported. These selected biphenyls and biphenyl ethers have IC50 values in the triple- to double-figure micromolar range.405 In context with stop-codon readthrough therapy, ataluren (115, Fig. 32), the aminoglycoside geneticin (116), a gentamicin-type compound, and others have been evaluated with best results obtained with compound 116.406,407 In context with experimental CMT, praziquantel derivatives have recently been mentioned.408

5.8 Lysosomal β-Glucuronidase Lysosomal β-D-glucuronidase (GUSB, EC 3.2.1.31) is a GH 2 retaining glycosidase that removes β-D-glucuronyl residues from the nonreducing end of heparin, dermatan, and keratan sulfates as well as of other structures.409,410

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OH H2N

OH

HO2C N

O

O

CH3

O

HO

NH2

OH

N O

F 115

O NH2

HO OH

H3C NHCH3

116

Fig. 32 Compounds 115 and 116.

The GUSB gene is located at chromosome 7 (7q11.21). The functional form of β-glucuronidase is homotetrameric with subunits of 75 kDa.411 It has four potential N-glycosylation sites, of which at least two have been found occupied.412 Structures of the human enzyme have been reported in 1996 (2.6 A˚ ˚ , PDB 3HN3).412 Contrary resolution, PDB 1BHG)413 and in 2013 (1.7 A to the bacterial β-D-glucuronidase from E. coli that shows 46% sequence identity, a loop of the bacterial enzyme (PDB 3LPG), which shows strong coordination with inhibitors, is completely missing in the human enzyme.412 Mutations on the GUS gene result in the lysosomal disease, Sly syndrome (MPS VII, OMIM# 253220)414 which is an ultra-rare disorder with an estimated global incidence between 1:300,000 and 1:2,000,000.367 Recently, the clinical fates of 56 cases from 11 countries have been reviewed.415 Of 211 mutations that may interfere with the stability of the enzyme, 90 were mapped and subjected to molecular dynamics simulations revealing five modifications with the highest impact on protein stability.416 Genistein (111) and other isoflavones, as well as combinations thereof, were found to decrease glycosaminoglycan storage levels at 50 μM in an approach to experimental SRT in human fibroblasts.417 The first human treatment with recombinant β-glucuronidase by biweekly infusions indicated good toleration and improvement of objective clinical measures and quality of life.418 Glucaro-1,4-lactone (101) and per-O-acetylated D-glucaro-1,4;3,6lactone were reported to be inhibitors of human β-glucuronidase.419,420 For D-glucaro-1,5-lactam (105), prepared by oxidation of nojirimycin [5-amino-5-deoxy-D-glucose (3)], an impressive Ki value of 39 nM was

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Carbohydrate-Processing Enzymes of the Lysosome

O O

HO2C

H N

NH

HO2C

N N

N N

HO

NH

HO HO HO

OH

O

HO OH

OH

118

119

117

HO

OH OH 120

Fig. 33 Imino sugar D-glucuronidase inhibitors 117–120.

CH3

OH

O

CH3

OH

O

OH

HO2C

121

CH3 CH2

CH3 OCOPh 122

Fig. 34 D-Glucuronidase inhibitors 121 and 122.

reported.421 Structurally related natural product 100 was found less potent by three orders of magnitude.318 Comparably active to the latter proved to be the ring-contracted analog 117 (Fig. 33).422 Isofagomine derivative 118 was found about as powerful as 423 D-glucaro-1,5-lactam (105) (Ki 79 nM). The same level of inhibitory power exhibited isofagomine lactam 119 (36 nM)424 as well as nojirimycinderived tetrahydrotetrazol 120 (25 nM).321 These values considerably exceed inhibitory activities of noncarbohydrates including coumarin derivatives such as 121 (IC50 10 μM, Fig. 34)425 or terpenoid natural product scoparic acid A (122) (IC50 7 μM).426 Investigation of these or related inhibitors for CMT of Sly syndrome has not been reported, as yet.

5.9 Lysosomal Hyaluronidase Lysosomal hyaluronidase (HYAL, EC 3.2.1.35), an endo-β-Nacetyl-hexosaminidase, is a GH 56 retaining hydrolase which degrades hyaluronan, a key component of the extracellular matrix in connective tissue. The encoding HYAL1 gene is located on chromosome 3 (3p21.31). The human enzyme is a 435-amino acid residue protein with activity in a

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H3C

COOH

H O O

CH3

O

H

10

HO2C

O HO

O

CH3

H H3C CH3

HO 123

CH3

O

O

HO

CH3

CH3

O

O

OH

CO2H

OH HO

OH OH 124

Fig. 35 Hyaluronidase inhibitors 123 and 124.

pH range between 3 and 4.5.427 Its N-terminal 325 amino acids exhibit 32% ˚ is sequence identity with bee venom hyaluronidase.428 A structure at 2.0 A 429 available (PDB 2PE4). N-Glycosylation at all three possible sites has been found to be essential for secretion as well as enzymatic activity.430 Interestingly, C-mannosylation was detected on Trp 130, a residue adjacent to the active site of intracellular hyaluronidase, but not in the secreted enzyme.431 Recombinant human enzyme has been expressed in various organisms including Drosophila and E. coli,432,433 as well as CHO cells (Hylenex™). Mutations in the HYAL1 gene cause mucopolysaccharidosis IX, also known as Natowicz disease.434 There is only a small number of inhibitors of hyaluronidase 1 known, such as 6-O-dodecanoyl-L-ascorbic acid (123) (Ki ¼ 50 μM, Fig. 35)432 or glycyrrhizic acid (124) (Ki 26 μM) and various plant extracts, the latter exhibiting lower activities.435

6. CONCLUSIONS AND OUTLOOK Despite the facts that quite a few lysosomal diseases and their causative molecular principles have been known for several decades and that research has gained considerable momentum turning toward applications, many white spots have remained on the map. Apart from difficulties of correct diagnosis, therapy offers have been limited and established patient-friendly

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treatment regimes are only available for a comparably small number of variants of these disorders. In context with CMT, the individual chemist may find many options to contribute to the improvement of our understanding of pharmacological chaperones for lysosomal diseases with clear and exciting options at the borderline between rare diseases and frequently occurring considerable burdens to individual quality of life as well as to society, such as senescence, Parkinson’s, and Alzheimer’s diseases. Not unlikely, “the greater lysosomal system”1 harbors quite a few additional connections between seemingly unrelated disturbed metabolic cycles and macroscopic disease symptoms. Screening procedures reported in the literature are quite heterogeneous, and frequently, it is difficult to compare scope and limitations of new compounds from different laboratories. In an attempt to create unified screening, at least at the level of inhibitory potencies, a new European platform has recently been founded. This compound collection and database coined “Glycomimetic Lead Factory” will soon be online and is currently in the early stages of pooling and screening compounds deposited by founding researchers and collaborators for activities with carbohydrate-processing enzymes. It will make the collected data available to the general public. With the aid of leading researchers and general acceptance by the community provided, unified protocols for more advanced investigations into compounds’ pharmacological properties might be at hand, providing a solid basis for broader comparison of potential carbohydrate mimicking pharmacophores in the not too distant future with sound options for development and beneficial exploitation of suitable compounds.

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