Repurposed Molecules: A New Hope in Tackling Neglected Infectious Diseases

C H A P T E R

5 Repurposed Molecules: A New Hope in Tackling Neglected Infectious Diseases Christopher Ferna´ndez-Prada*, Noelie Douanne*, Aida Minguez-Menendez*, Joan Pena*, Luiza G. Tunes†, Douglas E.V. Pires†, Rubens L. Monte-Neto† *

Pathology and Microbiology Department, University of Montreal, Saint-Hyacinthe, QC, Canada † Rene Rachou Institute, Belo Horizonte, Brazil

1 INTRODUCTION Infectious diseases have shaped the world as we know it. They have silently driven the evolution of many species and greatly influenced human civilization for centuries. According to the World Health Organization (WHO), infectious diseases are responsible for at least 15 million deaths worldwide each year. However, mortality is not the only factor to consider when measuring the burden of infectious diseases. Most researchers and medical organizations prefer to rely on disability-adjusted life years (DALYs) as a tool to draw a more realistic picture of the impact of infectious diseases. Neglected infectious diseases (NIDs) are a group of chronic, debilitating, and poverty-promoting diseases, which include parasitic, bacterial, viral, and fungal infections. NIDs thrive mainly among the most poverty-stricken populations and The Global Burden of Disease Study 2013 estimated that NIDs are among the world’s most common conditions, with more than 2 billion NIDs prevalent globally in 2013 (Herricks et al., 2017). While it was estimated that 141,800 deaths could be attributable to NIDs in 2013, their collective disease burden, estimated to reach 25 million DALYs, may be greater than the DALYs attributable to better known conditions such as tuberculosis (Hotez, Bottazzi, Franco-Paredes, Ault, & Periago, 2008) or liver cancer (Herricks et al., 2017).

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Despite these alarming figures, NIDs have been traditionally abandoned in terms of funding and policy, leading to an almost nonexistent development of therapeutic agents targeting these “forgotten pathogens.” Most of the few existing treatments for NIDs rely on “old fashioned” molecules that often present major obstacles and constraints. These include rapid emergence and spread of drug resistance, modest safety profiles, high costs, and the need for complex and supervised drug administration (Wyatt, Gilbert, Read, & Fairlamb, 2011). Furthermore, Big Pharma has shown a very limited interest in improving current therapeutics against NIDs because of the expected low return of investment when dealing with populations possessing little to no purchasing power (Berenstein, Magarinos, Chernomoretz, & Aguero, 2016; Robertson & Renslo, 2011). As a consequence of this failure to interest drug developers, less than 1% of the 1400 new drugs that reached the market between 1975 and 2000 were for the treatment of NIDs (Trouiller et al., 2002; Wyatt et al., 2011). This figure has improved slightly from 2000 to 2011. During the latter period, new drugs for NIDs reached 4% of the total drugs approved (Pedrique et al., 2013). However, all is not lost. The Drugs for Neglected Diseases initiative (DNDi), a nonprofit research and development organization founded by Medecins sans Frontie`res (MSF) and other public and private partners, has been advocating for change since 2004 in order to raise awareness of the NIDs crisis among key policy- and decision-makers (Pecoul, 2004). In addition, DNDi performs high-throughput untargeted screenings of novel-drugs libraries for NIDs as well as identifying new drug candidates using targeted compounds from repurposing libraries. In fact, this latter approach, repurposing of approved drugs, has become a very appealing strategy to tackle NIDs and is gaining supporters worldwide. Finding new indications for existing drugs has many benefits, mainly lower cost and a shorter time before marketing the drug (Chong & Sullivan Jr., 2007; DiMasi, Hansen, & Grabowski, 2003; Novac, 2013). Repurposing approved drugs helps avoid complications during clinical trials, such as drug toxicity or unfavorable pharmacokinetics (Zheng, Sun, & Simeonov, 2018). In this chapter we aim to explore the current situation of NIDs (Part I), discuss existing treatments and emerging challenges, and depict the different tools, approaches, and strategies that can be implemented to maximize the chances of effectively repurposing a drug for use against these neglected diseases (Part II). We close with a discussion of the potential impacts of drug repurposing on developing countries and some comments on future trends in the field.

2 PART I: CURRENT KNOWLEDGE AND CHALLENGES IN NEGLECTED INFECTIOUS DISEASES NIDs are a diverse group of communicable infectious diseases that threaten the life of more than one billion people in the world. Most affected people are from impoverished, underdeveloped, tropical, and subtropical countries. Although living and hygiene conditions are improving over time in these countries, the global impact of neglected tropical diseases remains substantial. The definition and classification of NIDs is not always clear and varies depending

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FIG. 1

Current classification and impact of neglected infectious diseases (NIDs) according to the WHO. NIDs are a heterogeneous group of infections caused by parasites, viruses, and bacteria that affect over a billion of the world’s poorest people and pose a significant social and economic burden to developing economies.

on the source consulted. In this chapter we will rely on the 17-disease list provided by WHO composed of two groups of parasite-driven diseases, including protozoan and helminth parasites, bacteria and viruses (see Fig. 1 for a detailed list).

2.1 Eukaryotic Neglected Infectious Diseases 2.1.1 Leishmaniases Leishmaniases are a group of vector-borne diseases caused by protozoan parasites belonging to the genus Leishmania. Among NIDs, leishmaniases rank second in mortality and fourth in DALYs. Leishmania parasites cycle between the motile promastigote form in the gut of the sand-fly vector and the intracellular amastigote stage within the macrophages of the host. Leishmaniases are endemic in at least four continents (88 countries), spanning tropical and subtropical regions of Central and South America, Africa, Asia, and the Mediterranean basin (Louzir et al., 2013; Tables 1 and 2).

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TABLE 1 Current and Prospective Drugs for Treatment of Parasitic Neglected Infectious Diseases Disease

Current Treatment

Repurposing Initiatives

Chagas disease

Benznidazole Nifurtimox

Metronidazole

Dracunculiasis

–

–

Echinococcosis

Albendazole Mebendazole Praziquantel

Tamoxifen Ursolic acid Amphotericin B

Foodborne trematodiases

Praziquantel Triclabendazole

Artemisinin derivatives Mefloquine OZ78 ozonide

Human African trypanosomiasis

Pentamidine Nifurtimoxeflornithine Suramin Melarsoprol

Diamidine derivatives Fexinidazole Oxaborole SCYX-7158 Quinolone amide GHQ 168 Tafenoquine

Leishmaniasis

Pentavalent antimonials Amphotericin Ba Miltefosinea Paromomycina

Camptothecin derivatives Indenoisoquinolinic compounds Auranofin

Lymphatic filariasis

Ivermectin Albendazole Diethylcarbamazine

Rifampicin combined with albendazole

Onchocerciasis

Ivermectin

Suramin Moxidectin

Schistosomiasis

Praziquantel Oxamnique

Artemisinin derivatives Mefloquine Piperaquine phosphate Trioxaquine PA1647 Nucleoside transport inhibitors combined with tubercidin or nebularine Acridine derivative Ro 15-5458 Nonsteroidal antiinflammatories Edelfosine

Soil-transmitted helminthiases

Albendazole Mebendazole Levamisole Pyrantel pamoate

Trichlorfon Bitoscanate Sertraline Paroxetine Chlorpromazine

Human taeniasis

Niclosamide Praziquantel Tribendimidine Albendazole

Paromomycin Quinacrine (Mepacrine) Tamoxifen

a

Drugs borne of past repurposing initiatives currently in use as treatments.

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TABLE 2

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Current and Prospective Drugs for Treatment of Bacterial and Viral Neglected Infectious Diseases

Disease

Current Treatment

Repurposing Initiatives

Buruli ulcer

Streptomycin and rifampicin

Avermectins (ivermectin, moxidectin, selamectin)

Chikungunya virus

–

Suramin

Dengue virus

–

Suramin Prochlorperazine

Leprosy

Rifampicin, clofazimine, and dapsone

Thalidomide

Rabies virus

–

–

Trachoma

Azithromycin

Mycophenolate mofetil

Yaws

Penicillin Azithromycin

–

In the absence of an effective vaccine, the control of leishmaniasis has traditionally relied on chemotherapy (Singh & Sundar, 2012), with a very limited number of registered molecules available. Moreover, significant drawbacks such as the complex route of administration, high toxicity, emergence of drug resistance, and astronomical costs limit their use in endemic areas (Sundar & Singh, 2018). The primitive and toxic pentavalent antimonials are the first choice of treatment and, in addition to their toxicity and long treatment schedules, they are frequently associated with drug resistance (Mohapatra, 2014; WHO, 2010). Strikingly, leishmaniasis is a great example in terms of drug repurposing. Amphotericin B (AmB) was first identified because of its antifungal activity and later repurposed against visceral leishmaniasis in the 1960s in Brazil (Furtado, Cisalpino, & Santos, 1960). More recently, AmB liposomal formulations were introduced for the treatment of visceral leishmaniasis in antimonial-nonresponsive regions of Bihar (India) (Ouellette, Drummelsmith, & Papadopoulou, 2004). While clinical resistance to AmB is rare (Lachaud et al., 2009), a recent study in India has reported an L. donovani field strain resistant to AmB (Srivastava, Prajapati, Rai, & Sundar, 2011). Another leishmanicidal drug introduced in the early 21st century is the alkyl-phospholipid analogue miltefosine (MF). MF was originally developed as a local treatment for cutaneous metastases of breast cancer and its oral formulation was evaluated in several phase II studies involving different types of solid tumors (Croft & Engel, 2006; Planting, Stoter, & Verweij, 1993; Verweij, Gandia, Planting, Stoter, & Armand, 1993). However, it was discontinued due to its side effects in cancer patients. In 1998 MF underwent phase II trials against leishmaniasis and showed promisingly high cure rates in the treatment of several forms of this NID (Sundar et al., 1998). Unfortunately, since its approval in 2002, it has had increasing relapse rates and there has been the emergence of drug-resistant strains (Bhattacharya et al., 2007; Sundar & Chakravarty, 2015). Sequential treatment of liposomal AmB followed by a short 7-day administration of MF has been introduced to fight antimony-resistant Leishmania populations in India (Olliaro, 2005, 2010). Unfortunately, a recent paper demonstrated the risk of emergence of cross-resistance between AmB- and MF-treated parasites in vitro (Fernandez-Prada et al., 2016).

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A third drug that was successfully repurposed in 2013 against Leishmania is the aminoglycoside-aminocyclitol paromomycin (Ben Salah et al., 2013), which was first isolated as a broad-spectrum antibiotic against Gram-positive and Gram-negative bacteria (Davidson, den Boer, & Ritmeijer, 2009). More recently, two different families of drugs have been proposed for repurposing against Leishmania. Both Food and Drug Administration (FDA)approved antitumor camptothecin derivatives and experimental indenoisoquinolinic compounds targeting the leishmanial DNA topoisomerase have shown great antileishmanial potential in both in vitro and in vivo models (Balana-Fouce et al., 2012; Prada, Alvarez-Velilla, Balana-Fouce, et al., 2013). Additionally, auranofin (2,3,4,6-tetra-O-acetyl-1-thio-β-Dglucopyranosato-S-[triethyl-phosphine]gold), an FDA-approved drug for use against rheumatoid arthritis and human dysentery, has been recommended as a candidate to be repositioned against Leishmania and has laid the foundation for possible exploitation of gold(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis (Sharlow et al., 2014). 2.1.2 Chagas Disease Caused by Trypanosoma cruzi, Chagas disease (a.k.a. American trypanosomiasis) is responsible for major public health concerns affecting 21 South American countries as well as a large portion of the southern United States (Bern, Kjos, Yabsley, & Montgomery, 2011). Recent reports show approximately 10 million new cases of infection and 14,000 deaths per year (Coura, 2015). This vector-born NID is normally transmitted by various species of three genera of blood-sucking triatomine insects, also known as kissing bugs. At the moment of infection, if the parasitic load is very high, the patient develops a highly dangerous acute phase that can lead to death. This acute phase generally lasts from 4 to 8 weeks. Parasitemia then decreases, resulting in a chronic condition that can lead to irreversible damage to the cardiac tissue, esophagus, and colon as well as major nerve damage to the aforementioned organs (Ferraz et al., 2018). Anti-Chagas treatment is always suggested for acute Chagas disease, reactivated infections, and chronic disease in children under 18 years. With regards to chronic infections, systematic review and metaanalysis showed that treatment had little to no benefit when compared with placebo (Perez-Molina et al., 2009). Strikingly, the annual cost of follow-up and medical care for those affected by Chagas is greater than 267 million (USD). Currently, only two compounds, benznidazole (since 1972) and nifurtimox (since 1967), are approved for the treatment of Chagas disease (Reyes & Vallejo, 2005). While both drugs are far from ideal in terms of toxicity and side effects, benznidazole is generally preferred over nifurtimox. In addition to toxicity, drug resistance has been raised as a major concern in terms of treatment failure and relapse (Campos, Leon, Taylor, & Kelly, 2014). Recently, metronidazole, a wellknown and safe nitroimidazolic derivative used as an antibiotic and antiprotozoal against anaerobic bacteria and parasites, such as Giardia or Trichomonas, has been included in repurposing initiatives against Chagas disease due to its high suitability for combinatorial treatments (Simoes-Silva et al., 2017). 2.1.3 Human African Trypanosomiasis Human African trypanosomiasis (HAT), or sleeping sickness, is a vector-borne parasitic disease endemic in sub-Saharan Africa. It is caused by protozoan parasites of the Trypanosoma

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brucei species, which are transmitted to humans via infected tsetse flies. HAT presents two stages of progression, from a hemolymphatic acute stage to a meningo-encephalitic chronic stage. Without treatment, HAT almost invariably progresses to death. Two different subspecies are responsible for human disease: T. brucei rhodesiense causes East African HAT (mainly acute infection), while T. brucei gambiense causes the West African form of the infection (mainly chronic HAT) (Kennedy, 2008). HAT prevalence has been profoundly influenced by the socio-economic uncertainties of endemic countries (Simarro, Jannin, & Cattand, 2008). Fortunately, thanks to sustained control efforts over the last two decades, the number of reported cases has fallen drastically. While approximately 300,000 cases were estimated in 1998, less than 3000 cases were reported in 2015 (Buscher, Cecchi, Jamonneau, & Priotto, 2017). The four main drugs available against HAT are very toxic; melarsoprol in particular kills 5% of treated patients (Kennedy, 2008). The choice of treatment varies according to both the stage of the disease and the infecting parasite. Pentamidine is used for S1 T. b. gambiense, nifurtimox-eflornithine for S2 T. b. gambiense, suramin for S1 T. b. rhodesiense, and melarsoprol for S2 T. b. rhodesiense (Carvalho et al., 2015; Chappuis, 2018; Tiberti & Sanchez, 2018). With the exception of suramin, alarming levels of drug resistance for all antiHATs have been detected in the field, especially for melarsoprol (Barrett, Vincent, Burchmore, Kazibwe, & Matovu, 2011). For this reason, various de novo drug discovery and drug repurposing initiatives are currently in development. These include several new leads involving diamidine derivatives, fexinidazole, oxaborole SCYX-7158, or quinolone amide GHQ168 (Berninger et al., 2018); as well as repurposed molecules like oral antimalarial tafenoquine, which has demonstrated impressive in vitro activity against T. brucei (Carvalho et al., 2015). 2.1.4 Human Taeniasis Human taeniasis is a complex zoonotic infection caused by the adult stages of Taenia saginata (beef tapeworm), Taenia solium (pork tapeworm), or Taenia asiatica (Asian tapeworm) (Hobbs et al., 2018; Okello & Thomas, 2017). Infection by accidental consumption of T. solium eggs from the environment can lead to aberrant encystment of the larval form (cysticercosis) in various locations within the human body, leading to cysts in subcutaneous and muscular tissue as well as in the eyes and central nervous system. The latter case, known as neurocysticercosis, has the greatest morbidity. Human taeniasis causes major health and socioeconomic problems in different regions of sub-Saharan Africa, South America, and South Asia. The 2010 Global Burden of Disease survey estimated that human cysticercosis caused by T. solium was responsible for 503,000 DALYs lost annually (Murray et al., 2012); 53 million people are currently infected, leading to about 28,000 deaths each year (Torgerson et al., 2015). Infections with the adult stage of Taenia spp. are responsive to the common anthelmintic drugs niclosamide, praziquantel, tribendimidine, and albendazole (reviewed by Okello & Thomas, 2017). In addition, mass drug administration (MDA) has been proposed as a suitable control strategy for human taeniasis either alone or in combination with other strategies, such as vaccination and anthelmintic treatment of the porcine host (Allan et al., 1997; Del Brutto et al., 1996; Sarti et al., 2000). Regarding drug development and drug repurposing against Taenia spp., several molecules have been investigated in recent decades. In this way, Salem and el-Allaf (1969) proved in the 1960s the taenicidal power of paromomycin, an antibiotic recently approved against Leishmania spp. (see above). Similarly, quinacrine (mepacrine),

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an ancient antimalarial drug used during World War II, has become a very interesting option to treat niclosamide-tolerant patients infected with T. saginata (Koul, Wahid, Bhat, Wani, & Sofi, 2000). Finally, tamoxifen, a well-known antitumor drug, has shown strong cysticidal and antitaeniasic effects on T. solium, which has encouraged the conducting of more studies on the subject (Escobedo, Palacios-Arreola, Olivos, Lopez-Griego, & Morales-Montor, 2013). 2.1.5 Echinococcoses Echinococcoses are parasitic diseases of major public health importance caused by larval stages of taeniid cestodes belonging to the genus Echinococcus (Kern et al., 2017). Within this genus, six species cause infections in humans (McManus, 2013). Among them, E. multilocularis and E. granulosus, the etiological agents of alveolar echinococcosis (AE) and cystic echinococcosis (CE), respectively, are the species of major importance in terms of public health concerns (Cadavid Restrepo et al., 2016). Larval development varies with species, leading to different degrees of disease severity (Nakao, Lavikainen, Yanagida, & Ito, 2013). Currently, around 2–3 million people are infected by AE or CE. This figure increases by a worrisome 200,000 new cases every year (reviewed by Cadavid Restrepo et al., 2016). In terms of DALYs, the burden of CE and AE reaches extreme annual values of approximately 285,407 and 666,434, respectively (Budke, Deplazes, & Torgerson, 2006; Torgerson, Keller, Magnotta, & Ragland, 2010). The treatment of echinococcosis varies according to the Echinococcus spp. involved, the size and location of the cyst(s) and the complications following an eventual rupture of said cyst(s). Normally, patients must undergo surgical removal of the cyst(s) accompanied by a course of chemotherapy lasting at least 2 years post surgery. For inoperable patients, chemotherapy remains the only option (reviewed by Hemphill & Muller, 2009). Current treatments rely on two benzimidazoles, albendazole and mebendazole, and the pyrazinoisoquinoline derivative, praziquantel. Considerable efforts have been undertaken to improve treatment options for CE and AE. These have involved ivermectin (Reuter, Manfras, Merkle, Harter, & Kern, 2006), different molecules from the Malaria Box (Stadelmann et al., 2016), and several kinase-inhibitors ( Joekel, Lundstrom-Stadelmann, Mullhaupt, Hemphill, & Deplazes, 2018). Unfortunately, most of these repurposing initiatives have fallen by the wayside because of their poor in vivo results. On a more positive note, three FDA-approved drugs have been recently proposed as highly repurposable candidates: (1) antitumor drug tamoxifen, which is effective against adult forms and cysts of E. granulosus (Nicolao, Elissondo, Denegri, Goya, & Cumino, 2014); (2) ursolic acid, which is highly active against different stages of E. granulosus, both in vitro and in vivo (Yin, Liu, Shen, Zhang, & Cao, 2018) and; (3) antileishmanial amphotericin B, which could be extremely useful in the case of drug resistance or intolerance to benzimidazoles in AE infections (Reuter et al., 2003). 2.1.6 Schistosomiasis In terms of morbidity and mortality, schistosomiasis is considered the most important helminth-borne disease affecting human beings (Disease and Injury Incidence and Prevalence Collaborators, 2016). This NID is primarily caused by three species of trematode worms of the genus Schistosoma: S. mansoni and S. japonicum, which cause hepato-intestinal schistosomiasis; and S. haematobium, which causes urogenital schistosomiasis (Ross et al., 2002). Infection occurs when people are exposed, during routine domestic, agricultural, occupational, and recreational activities, to the larval forms of the parasite (released by freshwater snails) that

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contaminate freshwater sources. Schistosomiasis currently affects 240 million people in 74 developing countries, causing a loss of 10.4 million DALYs (King, 2010). Given the absence of an effective vaccine, praziquantel is the mainstay of treatment and a critical part of community-based schistosomiasis control programs (Caffrey, 2007), in addition to environmental and behavioral modification (Ross et al., 2002). Praziquantel is currently administered to more than 100 million people each year (Kuntz et al., 2007), which has raised the alarm for the emergence of drug resistance (Doenhoff, Cioli, & Utzinger, 2008; Gryseels, Polman, Clerinx, & Kestens, 2006). Until recently, oxamnique, a semisynthetic tetrahydroquinoline, was the drug of choice against S. mansoni in Brazil (Fenwick, Savioli, Engels, Robert Bergquist, & Todd, 2003) and has been proposed for combinatorial treatment with praziquantel (Gouveia, Brindley, Gartner, Costa, & Vale, 2018). However, the results derived from various clinical trials are inconclusive and further studies on the subject are necessary. Several drugs have been tested against schistosomiasis, either alone or combined (reviewed by Gouveia et al., 2018). While artemisinin derivatives (artemether, artesunate, and dihydroartemisinin) demonstrate significant activity against juvenile infections (Keiser & Utzinger, 2012), mefloquine has proven to target both juvenile and adult parasites (Panic, Duthaler, Speich, & Keiser, 2014). Two other antimalaria drugs that are currently in the spotlight are piperaquine phosphate (Synriam) and trioxaquine PA1647. Administration of the former led to a less severe liver pathology in S. mansoni infections (Mossallam, Amer, & El-Faham, 2015), whereas the latter showed an additive or synergistic effect against juvenile forms when combined with praziquantel (Portela et al., 2012). Gouveia and co-workers reviewed several interesting combinations of drugs with praziquantel to determine their activity against different forms of schistosomiasis. The drugs included nucleoside transport inhibitors, especially NBMPR-P or dialazep, in combination with tubercidin or nebularine (el Kouni, Messier, & Cha, 1987); acridine derivative Ro 15-5458 (Kamel, Metwally, Guirguis, Nessim, & Noseir, 2000); nonsteroidal antiinflammatory agents, such as ibuprofen and naproxen (Mahmoud, Zoheiry, & Nosseir, 2002); and synthetic lipid edelfosine (Yepes et al., 2014), among others (Gouveia et al., 2018). 2.1.7 Food-Borne Trematode Infections Humans are afflicted by numerous parasitic food-borne zoonoses, most of which are caused by trematodes. Trematodes have indirect and complicated life cycles involving different larval stages, two nonhuman intermediate hosts, and a definitive mammalian host. Agents of food-borne trematode infections include liver flukes (clonorchiasis, opisthorchiasis, and fascioliasis), lung flukes (paragonimiasis), and intestinal flukes (diplostomiasis, echinostomiasis, fasciolopsiasis, gymnophalloidiasis, and heterophyiasis) (Furst, Keiser, & Utzinger, 2012; Toledo, Esteban, & Fried, 2012). In terms of public health, food-borne trematode infections are responsible for more than 200,000 new infections and more than 7000 deaths each year. Recent estimates indicate that more than 40 million people are currently infected, leading to a global burden of 665,352 DALYs (Keiser & Utzinger, 2005, 2009; Sripa, Kaewkes, Intapan, Maleewong, & Brindley, 2010; Toledo, Bernal, & Marcilla, 2011). Praziquantel is the molecule of choice for treatment of all food-borne trematodiases (Keiser & Utzinger, 2004), except for fascioliasis, which is effectively treated with triclabendazole (reviewed by Toledo et al., 2012). Due to the low cure rate found in a study with praziquantel

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in Vietnam (Tinga et al., 1999), as well as established triclabendazole drug resistance in veterinary medicine (Keiser & Utzinger, 2004), there are concerns drug resistance may become problematic. This spurs the search for new alternatives. Along those lines, two artemisinin drugs, artemether and artesunate, have been successfully tested against liver flukes in rodent models (Panic et al., 2014). Another antimalaria drug, mefloquine, was effective against different stages of liver fluke in hamster models (Keiser, Duthaler, & Utzinger, 2010). However, these promising results were not translated to humans in clinical trials (Soukhathammavong et al., 2011). Finally, OZ78 ozonide, an analog of synthetic peroxide, has proved effective against triclabendazole-resistant F. hepatica in rat models (Keiser et al., 2007). 2.1.8 Lymphatic Filariasis Lymphatic filariasis is a mosquito-borne NID that represents a major public health problem in 74 countries due to its association with substantial morbidity and disability (Ramaiah & Ottesen, 2014). Lymphatic filariasis, caused by Wuchereria bancrofti, causes severe damage to the lymphatic system, frequently leading to elephantiasis (lymphedema) and hydrocele. WHO estimates 25 million men are currently affected with filarial-borne hydrocele and over 15 million people with lymphedema, and ranks lymphatic filariasis as one of the world’s leading causes of permanent and long-term disability (WHO, 2017a). In addition, Ton, Mackenzie, and Molyneux (2015) calculated in the ranks of 5.09 million DALYs the burden of depression attributable to filariasis, which doubles previous calculations by the Global Burden of Disease Study of 2010. In order to tackle this disease, The Global Program to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000. GPELF relies on MDA of three anthelmintics: ivermectin, albendazole, and diethylcarbamazine. Albendazole is used in combination with ivermectin in Africa, whereas combination with diethylcarbamazine is approved for use in areas where filariasis is not endemic. Unfortunately, these drugs are incapable of eliminating adult worms, and the strong selective pressure on parasite populations due to MDA could lead to drug-resistant strains (Cobo, 2016). Recently, targeting the essential filarial endosymbiont Wolbachia was proposed as a suitable strategy to tackle this NID. Turner and co-workers demonstrated that the combination of albendazole and rifampicin depleted endosymbionts after a 7-day course of treatment, leading to accelerated macrofilaricidal activity (Turner et al., 2017). Importantly, these results represent a solid validation of previous in vitro screens aimed at the repositioning of different FDA-approved drugs against Wolbachia endosymbionts in order to implement novel regimes for macrofilaricidal therapy ( Johnston et al., 2014). 2.1.9 Onchocerciasis “River blindness,” or human onchocerciasis, is a vector-borne NID caused by the filarial nematode Onchocerca volvulus, transmitted by blackflies from the genus Simulium (Udall, 2007). During the infection, O. volvulus male adults move through subcutaneous tissue and skin, causing intense pruritus, skin lesions, and disfigurement. Meanwhile, female adults produce microfilariae with significant preference for the eyes, resulting in visual impairment and blindness (Babalola, 2011). Recently, the burden of this NID has been related not only to a lower quality of life, but also to an increase in mortality (Walker et al., 2012). About 37 million people are currently infected. Of those infected, 300,000 have been blinded by this NID and a

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further 500,000 are visually impaired. The estimated cost of the disease in 2015 was 1.1 million DALYs (DALYs & HALE Collaborators, 2016). Current treatment of onchocerciasis relies on ivermectin, an anthelminthic widely used in veterinary and human medicine. Unfortunately, ivermectin can merely control progression of this disease; the drug’s very limited effects on microfilariae prevent it from completely blocking infection (Omura & Crump, 2004). Additionally, drug resistance is ever-present, especially in the case of ivermectin. Regarding this issue, suramin has been recently repurposed and approved to fight O. volvulus, but its toxicity and availability interfere with its success. Another promising option is moxidectin, which has reached phase II trials after its activity and safety was demonstrated (Udall, 2007). Similar to the mechanism proposed for lymphatic filariasis (see above), several repurposing strategies targeting Wolbachia endosymbionts are currently in development ( Johnston et al., 2014). 2.1.10 Soil-Transmitted Helminthiasis Soil-transmitted helminthiasis (STH) is an NID caused by several genera of intestinal worms transmitted to humans through contaminated soil, either by accidental consumption of infective eggs/larvae (roundworms and whipworms), or by active penetration through the skin (hookworms). The four main nematode species that infect humans are Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and Necator americanus and Ancylostoma duodenale (hookworms). Helminthiases cause blood loss, anemia, malnutrition, intellectual impairment, and cognitive development problems (Pabalan et al., 2018). STH is the most frequent NID, currently affecting about 1.45 billion people worldwide. The global burden of STH was estimated at 3.4 million DALYs in 2015 (DALYs & HALE Collaborators, 2016). Nowadays, STH treatment relies on several anthelmintic medicines, including albendazole and mebendazole as first-line drugs, and levamisole and pyrantel pamoate as second-line. In fact, albendazole is the sole drug effective against all four parasites, being the only treatment active against hookworms. Moreover, all these drugs present important performance issues, especially against T. trichiura (Moser, Schindler, & Keiser, 2017). In order to alleviate this problem, drug repurposing possibilities must be urgently explored to find new effective compounds. For instance, antitumor drugs—protein kinase inhibitors in particular—have shown interesting anthelmintic potential in vitro. However, in vitro results did not necessarily translate into successful in vivo tests, thus hindering further repurposing of these drugs for STH (Cowan, Raimondo, & Keiser, 2016). Additionally, libraries of FDA-approved compounds are being currently tested in clinical and preclinical trials against STH infections. Results showed interesting anthelminthic properties for trichlorfon and bitoscanate (Keiser et al., 2016), as well as sertraline, paroxetine, and chlorpromazine, which could substitute or complement existing drugs in drug-resistance scenarios (Weeks et al., 2018). 2.1.11 Dracunculiasis Dracunculus medinensis, or the so-called “Guinea worm,” is the etiological agent of dracunculiasis, a crippling parasitic NID. D. medinensis worms affect communities in rural, deprived, and isolated areas that depend on open-surface water sources for drinking water and irrigation (Tayeh, Cairncross, & Cox, 2017). Despite this disease being present in many tropical countries, with a prevalence of approximately 3.5 million cases in 1985, eradication programs

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had reduced this figure to 30 confirmed cases in 2017. According to provisional reports issued by WHO, in the first quarter of 2018, only three cases of human dracunculiasis were reported, all of them in Chad. In terms of mortality, Guinea-worm disease is rarely fatal. Frequently, however, the patient remains sick for several months due to the pathology (and severe morbidity) caused by these parasites, mainly triggered by the migration (sometimes in aberrant locations), emergence, and accidental rupture of the worm (Greenaway, 2004; Lupi et al., 2015). Currently, the only effective treatment for dracunculiasis is the painful and laborious technique of winding the emerging worm around a piece of gauze or small stick to manually remove the parasite. In the 1970s, before the massive eradication campaign was begun, several anthelminthic compounds, such as metronidazole, were studied as a treatment against dracunculiasis (Antani, Srinivas, Krishnamurthy, & Borgaonkar, 1972; Pardanani & Kothari, 1970). However, results were unsatisfactory and, consequently, the repurposing initiative was rapidly abandoned. Likewise, a more recent study by Eberhard, Brandt, Ruiz-Tiben, and Hightower (1990) evaluated the potential use of diethylcarbamazine, albendazole, and ivermectin against dracunculiasis with similar outcomes as those observed for metronidazole.

2.2 Bacterial NIDs 2.2.1 Buruli Ulcer Buruli ulcer (BU) is a chronic skin infection caused by the bacteria Mycobacterium ulcerans. This disease is present in more than 33 countries of tropical and subtropical climate. The mode of transmission of M. ulcerans is unknown. The disease starts as a painless nodule or plaque that, without treatment, can cause necrotizing ulceration leading to permanent deformities and disability. In 2004 WHO established a treatment protocol using streptomycin and rifampicin in addition to surgery. This protocol is effective in cases of early, limited disease (Nienhuis et al., 2010). Recently, two avermectins, ivermectin and moxidectin, were tested in repurposing trials against BU in order to reduce reliance on streptomycin as well as its side effects (Omansen et al., 2015). In addition to a synergistic killing effect with rifampicin, Omansen et al. (2015) in vitro findings highly suggest that avermectins should be further evaluated for the treatment of M. ulcerans, particularly in combination with different families of antibiotics, such as fluoroquinolones. Similarly, Scherr, Pluschke, Thompson, and Ramon-Garcia (2015) tested the family of commercially available macrocyclic lactones against M. ulcerans and demonstrated that selamectin is a very promising avermectin candidate for anti-BU treatment. Interestingly, selamectin is already approved for veterinary treatment, which may accelerate its progression into clinical trials. Very recently, a library of compounds from a drugdevelopment program against tuberculosis was screened against M. ulcerans. Promisingly, Scherr, Pluschke, and Panda (2016) found five leads with high anti-BU activity, demonstrating that screening of libraries targeting related diseases is a good starting point for lead generation/repurposing. Finally, Malhotra, Mugumbate, Blundell, and Higueruelo (2017) released TIBLE (www-cryst.bioc.cam.ac.uk/tible/), a web-based, freely accessible resource

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for small-molecule binding data for mycobacterial species, which represents a major source of information to assist in drug development and repurposing against Mycobacterium species. 2.2.2 Leprosy (Hansen’s Disease) Leprosy is an ancient disease, caused by infection with the bacillus Mycobacterium leprae. It is present in 136 countries on all six continents and affects around 200,000 people each year. Three countries are responsible for 80% of cases: Brazil, India, and Indonesia (WHO, 2017c). Controlling this disease is a difficult task, mainly because its transmission is still poorly understood, diagnosis is difficult, and patients delay or refuse to seek health care for fear of the stigma (Steinmann, Reed, Mirza, Hollingsworth, & Richardus, 2017). Leprosy, or erythema nodosum leprosum, affects mainly the skin and peripheral nerves, causing nerve damage and nerve function impairment that can lead to deformity and disability. People affected by leprosy can be limited in the use of their limbs, restricted with regards to social activities, and suffer from substantial social stigma and discrimination, all of which contributes to economic loss (van Brakel et al., 2012). The first drug systematically used to treat leprosy in the 1940s was dapsone, also known as diaminodiphenyl sulfone (DDS) (Noordeen, 2016). However, DDS had weak bactericidal activity and treatment took years, which reduced patient compliance. For that reason, resistance to DDS rapidly increased and by the 1960s DDS monotherapy was no longer possible. In 1981, WHO established a multidrug therapy protocol using rifampicin, clofazimine, and dapsone. This multidrug therapy is still in use, but has several limitations including high cost, questionable efficacy, potential adverse effects, and length of treatment (2-year regimen) (Smith et al., 2017). The importance of finding new drugs to treat leprosy is indisputable. Although M. leprae is susceptible to a wide range of antibiotics, the inability to grow this bacillus axenically is a major drawback to drug discovery. An interesting example of drug repurposing against leprosy is thalidomide, which become one of the first drugs approved for this indication (Baek, Jung, Kang, Lee, & Bae, 2015). This drug was first marketed as a sedative and as a treatment for morning sickness in pregnant women (Costa et al., 2018). However, thalidomide presents major caveats, such as the risk of teratogenicity and neurotoxicity, which forced its withdrawal from the market (Anon., 1962). 2.2.3 Trachoma Trachoma is an ocular infection caused by the intracellular bacteria Chlamydia trachomatis. It is transmitted by direct contact with infected ocular secretions, especially among children. Around 192 million people are at risk of contracting trachoma and 450,000 are irreversibly blind (Satpathy, Behera, & Ahmed, 2017). The control strategy endorsed by WHO since 1993, called SAFE, consists of surgery for preventing blindness in patients with trichiasis, treatment with antibiotics to reduce the reservoir of C. trachomatis, facial cleanliness, and environmental safety measures to reduce transmission (WHO, 2017c). Azithromycin is the current treatment for trachoma. WHO recommends between three and five annual MDA to entire communities, aiming to treat individual cases of infection, reduce the reservoir, and interrupt transmission. Given that the logistics of treating entire communities in remote areas are complicated and that the number of rounds and doses of treatment has not been systematically established, MDA is still unable to eliminate transmission of this disease

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(Last et al., 2017). Despite the lack of concrete evidence for C. trachomatis resistance to azithromycin, there is a concern for the development of antimicrobial resistance since some communities still present persistent infection even when using multiple rounds of MDA (West et al., 2014). There are several reports of in vitro C. trachomatis resistance to rifamycins, macrolides, and quinolones, increasing the concern for development of clinical resistance (Sandoz & Rockey, 2010). An interesting alternative to traditional drug treatment is the development of host-directed therapies against C. trachomatis. In this way, Rother et al. (2018) integrated human genome-wide RNAi and metabolomics analyses to explore the growth requirements and signaling pathways essential for C. trachomatis. The authors found an extremely interesting target, the inosine-50 -monophosphate dehydrogenase 2, which is specifically inhibited by the clinically approved and well-studied drug mycophenolate mofetil. The aforementioned would make an excellent candidate for repurposing against trachoma. 2.2.4 Yaws Yaws, a chronic skin, bone, and cartilage infection, is caused by the bacteria Treponema pertenue. This microorganism is a subspecies of Treponema pallidum that is responsible for venereal syphilis as well as chronic pinta in South America (Stamm, 2015a). Treponematoses are endemic in warm, humid, and tropical forest areas of Africa, Asia, Latin America, and the Pacific. The affected population is usually isolated, with limited access to health care (Marks, Mitja, Solomon, Asiedu, & Mabey, 2015). In 2012, WHO’s strategy for the eradication of yaws recommended MDA with single doses of azithromycin followed by ongoing active surveillance in affected communities. Although this strategy greatly reduced the burden of this disease in different yaws-endemic island populations, many cases are reported in communities spread over a contiguous land mass, where MDA approaches are more difficult (Abdulai et al., 2018). If left untreated, yaws may progress to multiple skin lesions, bone and cartilage inflammation, tissue necrosis, and disfigurement (Marks et al., 2015). Treatment has, for over 50 years, consisted of a single dose of long-acting, injectable penicillin. Even with such extensive use, there are no reports of resistance. In 2012, a study evidenced that a single dose of oral azithromycin (30 mg/kg) is as effective as penicillin (Mitja et al., 2015). Given the widespread resistance to azithromycin in sexually transmitted strains of T. pallidum, the risk of T. pertenue also developing resistance must be considered (Stamm, 2015b). Indeed, five cases of clinical failure of azithromycin were reported in a village in Papua New Guinea. The patients were infected with a T. pertenue strain carrying mutations associated with macrolide resistance in the 23s rRNA gene, suggesting the emergence of resistance to azithromycin (Mitja et al., 2018).

2.3 Viral Diseases 2.3.1 Dengue Dengue is a fast-emerging viral disease that is transmitted to humans through bites of Aedes aegypti mosquitoes. Dengue is widespread in more than 100 countries of tropical and subtropical regions. The exact burden of this disease is uncertain because many cases go unreported, yet, in 2015 alone, there were a known 3.2 million cases (WHO, 2017c).

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Infection with dengue virus has a wide clinical spectrum that can vary from asymptomatic to severe hemorrhagic fever progressing to death (McFee, 2018). There is no specific treatment for dengue, only management of symptoms. Maintaining the patient’s circulating fluid volume is the most important strategy of care in severe cases. Promising drug candidates are being developed, but the four different serotypes of dengue virus and the fact that treatment is expected to inhibit all of them poses a challenge to drugdiscovery research (Tian, Zhou, Takagi, Kameoka, & Kawashita, 2018). In terms of drug repurposing, suramin (a drug marketed to fight river blindness) showed important inhibitory properties against dengue virus’ helicase in a high-throughput study of 1600 compounds (Basavannacharya & Vasudevan, 2014). Another example is prochlorperazine, a drug formulated to treat nausea, vomiting, and headache [very similar to the major symptoms of dengue virus ( Jones et al., 2011)], which recently demonstrated a promising ability to block dengue infection and improve symptoms at nontoxic doses (Simanjuntak, Liang, Lee, & Lin, 2015). 2.3.2 Chikungunya Chikungunya is a viral disease that has emerged as an epidemic threat over the past 15 years (Tharmarajah, Mahalingam, & Zaid, 2017). It is transmitted by mosquitoes of the Aedes genus and affects over one million people yearly. Chikungunya occurs in tropical regions and major outbreaks reported globally in the 2000s caused great strain on affected areas (Ganesan, Duan, & Reid, 2017). The symptoms of chikungunya infection are fever, rash, and debilitating joint pain that can progress to a chronic state and last from months to years. Consequently, chikungunya virus is associated with low mortality and high morbidity. Like dengue, there is no specific treatment for this disease and health care is focused on management of symptoms, usually using nonsteroidal antiinflammatory drugs. There are studies describing inhibitors of chikungunya virus using known antivirals or new molecules; however, those drug candidates still need to be validated in in vivo models of the disease (Tharmarajah et al., 2017). These include the abovementioned suramin, which is currently approved to treat onchocerciasis and is under investigation for use against dengue virus. Interestingly, suramin has shown considerable activity against chikungunya virus (Albulescu et al., 2015; Henss et al., 2016; Ho et al., 2015). Because treatment only requires administering this (otherwise toxic) drug for a short period of time, suramin appears to be a promising candidate for continued studies. 2.3.3 Rabies Rabies is a fatal viral infection that kills around 60,000 people each year according to WHO. The transmission of this disease occurs mainly through bites from infected dogs. Rabies is present in 150 countries, affecting especially Asia and Africa. Because it is an underreported disease, the true incidence and burden of rabies is unknown (Fisher, Streicker, & Schnell, 2018; WHO, 2017b). Human rabies is 100% preventable by vaccination and can be treated using vaccine therapy and immunoglobulin. However, the treatment is only effective if administered early and quickly to bite victims, which is difficult for patients in remote areas ( Jackson et al., 2003). In such circumstances, it would be beneficial to have promptly available drugs. There are reports of antiviral compounds that were effective in vitro, but none have as yet been proven to have enough efficacy to be used clinically (Smreczak et al., 2018).

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3 PART II: TOOLS AND STRATEGIES 3.1 Useful Databases for Drug Repurposing in Neglected Infectious Diseases Drug-repurposing pipelines benefit from different methods in computational pharmacology that integrate multiple databases, each playing a critical role in the efficient translation of basic science to therapeutics. These transforming tools enable new and exciting links among different fields, such as medicinal chemistry, bioinformatics, drug discovery, systems biology, and genomics. Current databases contain a vast variety of information related to, among others, drug structures, drug-target interactions (DTI), drug-disease associations, phenotypic drug screens, and functional genomics. This section will describe some of these databases, not with the intention of providing a comprehensive list, but rather to highlight new and recently updated high-quality resources for drug repurposing (these are summarized in Table 3). TABLE 3 Useful Databases for Drug Repurposing in Neglected Infectious Diseases Resource Type

Resource

General PubChem databases for drug information

Drug-target interactions

Genomic resources

Description

URL

References

Database of chemical structures, https://pubchem. identifiers, chemical and physical ncbi.nlm.nih.gov properties, biological activity, etc. (95M compounds)

Kim et al. (2016)

ChEMBL

Database of structures, calculated https://www.ebi.ac. properties and abstracted bioactivities uk/chembl/ (1M compounds)

Bento et al. (2014)

DrugBank

Database of drug data and target information. Drug clinical and repurposing trials

Wishart (2007), Wishart et al. (2006, 2018), and Wishart and Wu (2016)

CDD

Collaborative web-based database that http://www. contains thousands of drug structures collaborativedrug. and bioactivity data com/

www.drugbank.ca

Hohman et al. (2009)

BindingDB Database of binding affinities, interactions of drug-target proteins. Integrates information from multiple databases

www.bindingdb.org

Chen et al. (2001)

STITCH

Information about metabolic pathways, crystal structures, binding experiments, and drug-target relationships

http://stitch.embl. de/

Kuhn et al. (2008)

TDR Targets Database

Tool for the identification and http://tdrtargets.org prioritization of drugs and drug targets in neglected infectious diseases

Aguero et al. (2008)

GeneDB

Genome sequences and annotated data www.genedb.org for prokaryotic and eukaryotic pathogens

Logan-Klumpler et al. (2012)

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TABLE 3 Resource Type

Useful Databases for Drug Repurposing in Neglected Infectious Diseases—cont’d Resource

Description

EuPathDB

Collection of databases of eukaryotic http://eupathdb.org pathogens and selected pathogen hosts

Aurrecoechea et al. (2017)

Standard set of true positives (approved drugs) and true negatives (failed drugs)

http://apps. chiragjpgroup.org/ repoDB/

Brown and Patel (2017)

Clinical Trials

A registry and results database of 274,049 clinical studies with human participants in 204 countries

www.ClinicalTrials. gov

McCray and Ide (2000)

SIDER

Database of drugs and adverse druf reactions (ADRs). 1430 drugs, 5880 ADRs and 140,064 drug-ADR pairs

http://sideeffects. embl.de

Kuhn et al. (2016)

Offsides database

Complement resource to SIDER. 438,801 off-label side effects for 1332 drugs, and 10,097 ADRs

http://tatonettilab. org/resources/ tatonetti-stm.html

Tatonetti et al. (2012)

Drug-disease RepoDB associations

Drug-side effect associations

URL

References

If we take the compound as the starting point for any repurposing pipeline, PubChem (Kim et al., 2016) and ChEMBL (Bento et al., 2014) represent two major databases encompassing biomolecules and their activities. PubChem contains the largest collection of publicly available chemical information (95 M compounds, comprising both small and large molecules), including chemical structures, identifiers, chemical and physical properties, biological activity, toxicity data, etc. (Kim et al., 2016). ChEMBL, a manually curated database, is focused on bioactive drug-like small molecules and contains structures (1 M compounds), calculated properties, and abstracted bioactivities. The latter are frequently normalized into a uniform set of end-points and units. ChEMBL often tags the links between a molecular target and a published assay with a set of varying confidence levels (Bento et al., 2014), a useful feature. In addition, ChEMBL is currently integrating additional data on the clinical progress of compounds, which will provide important information for selecting and characterizing repurposed drug candidates with a particular focus on guaranteeing human safety (Corsello et al., 2017). Moving forward in the repurposing pipeline requires a precise identification of DTIs and a complete elucidation of the functional response of the target molecule. Depending on the chosen database, one can retrieve different levels of DTI information. An example is DrugBank (Wishart, 2007; Wishart et al., 2006, 2018; Wishart & Wu, 2016), an exceptional bio/ cheminformatics database that brings together detailed drug information with compressive drug target data. Interestingly, its recent 5.0 version integrates novel “pharmaco-omic” data describing the influence of drugs on metabolite levels and levels of gene and protein expression. Moreover, this up-to-date tool now includes the results of hundreds of investigational drug clinical trials and various repurposing trials (Wishart et al., 2018). Another major public, web-accessible resource in terms of DTI is BindingDB (Chen, Liu, & Gilson, 2001). This database compiles and structures binding affinities, focusing mainly on the interactions of

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proteins considered to be drug targets (more than 7225) with small, drug-like molecules (more than 621,060). In addition, BindingDB integrates information from other databases, such as confirmatory BioAssays from PubChem or ChEMBL, entries for which a well-defined protein target is provided, as well as links to experimentally solved protein structures and protein-ligand complexes, when available, at the Protein Data Bank (Chen et al., 2001; Gilson et al., 2016; Liu, Lin, Wen, Jorissen, & Gilson, 2007; Wassermann & Bajorath, 2011). Collaborative Drug Discovery (CDD), a spin-out of Eli Lilly, created a key tool for drug repurposing against NIDs. CDD is a collaborative web-based database that contains thousands of drug structures and bioactivity data (Ekins, Williams, Krasowski, & Freundlich, 2011). However, the major strength of this tool is to allow the user to perform sophisticated structure-activity relationship (SAR) analysis, including chemical pattern recognition, physical-chemical property calculations, and Boolean search, and to save capabilities for potency, selectivity, toxicity, and other experimentally derived properties (reviewed by Hohman et al., 2009). While efforts to integrate data are increasing, information on interactions between proteins and drug-like small molecules spans a massive number of databases that differ in structure, information content, and prediction methods, making it very difficult to understand the current level of evidence. In order to address this issue, Kuhn, von Mering, Campillos, Jensen, and Bork (2008) developed STITCH, a database that integrates information about interactions from metabolic pathways, crystal structures, binding experiments, and drug-target relationships of known and predicted interactions between chemicals and proteins. Interestingly, in the latest version of STITCH, a very useful binding-affinity network view has been implemented that allows the user to rapidly identify the different potential effects of the molecule in its interaction network (Szklarczyk et al., 2016). This feature is especially relevant in drug repurposing as the pathways or protein complexes affected may differ when targeting a different pathogen. Genetic studies represent a major source of information for the identification of drug targets and may increase the likelihood of drug repurposing success (Pritchard, O’Mara, & Glubb, 2017). In this way, researchers devoted to tackling neglected tropical diseases can take advantage of the Tropical Disease Research (TDR) Targets Database, a powerful tool that exploits the availability of diverse data sets to facilitate the identification and prioritization of drugs and drug targets in neglected disease pathogens (Aguero et al., 2008). In fact, TDR Targets serves as an excellent tool for prioritization of targets in whole genomes as it allows users to assess the role of a defined gene in the biology of the pathogen, as well as to predict whether pharmacological targeting of this role is likely to kill the pathogen (Magarinos et al., 2012). In addition to its team’s curatorial efforts, TDR Targets integrates other primary data sources such as the abovementioned ChEMBL, DrugBank, and PubChem, in addition to data collected from several high-throughput screening initiatives (Magarinos et al., 2012). Based on TDR Targets’ predictions, Fernandez-Prada and co-workers pinpointed the DNA topoisomerase IB of Leishmania infantum, the etiological agent of NID visceral leishmaniasis, as a promising target for drug intervention due to its unique nature and structural differences with regard to its mammalian counterpart (Prada et al., 2012; Prada, Alvarez-Velilla, DiazGozalez, et al., 2013). These authors assessed in vitro and ex vivo the leishmanicidal activity of three camptothecin analogues used in cancer therapy. Strikingly, one of the compounds, gimatecan (ST1481), an orphan drug (EU/3/03/174) used in the treatment of glioma (Teicher, 2008), demonstrated an extraordinary leishmanicidal power and a therapeutic selectivity

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index threefold higher than that observed for the antileishmanial drug miltefosine (Prada, Alvarez-Velilla, Balana-Fouce, et al., 2013). More recently, Berenstein et al. (2016) used the TDR Targets Database to construct a multilayer network of protein targets, chemical compounds, and their relations to guide drug-discovery/positioning efforts against neglected diseases. Networks represent a natural framework to integrate an extensive diversity of data sources, identifying and quantifying relationships between entities (e.g., gene expression correlation, or the existence of a defined interaction) (Martinez, Navarro, Cano, Fajardo, & Blanco, 2015). Interestingly, some of the candidates predicted by this network model were supported by independent experimental validations; such as in the case of the orphan compound (TDR Targets ID 599594), active against the malarial agent Plasmodium falciparum, which was connected by the network model to several hydroxamic acid derivatives that are known to inhibit bacterial peptide deformylases (Berenstein et al., 2016). Using this method, actinonin (Wiesner, Sanderbrand, Altincicek, Beck, & Jomaa, 2001), a widely used peptide-deformylase inhibitor, as well as other hydroxamates, have shown promising antimalarial power (Hynes, 1970). This highly valuable network-based tool provides a cohesive view of repurposing strategies by enabling a better prioritization of drug targets as well as a superior identification of potential targets for orphan bioactive drugs (Berenstein et al., 2016). GeneDB (Logan-Klumpler et al., 2012) and EuPathDB (Aurrecoechea et al., 2017) are two major databases that can enhance drug repurposing opportunities through a better understanding of pathogens’ genetics. While not restricted to NIDs, many neglected pathogens are covered by these two highly interconnected genomic tools. GeneDB is one database that provides a portal to genome sequence and annotation data for prokaryotic and eukaryotic pathogens as well as closely related organisms. This data is mainly produced by the Pathogen Genomics group at the Wellcome Trust Sanger Institute (Logan-Klumpler et al., 2012). Another example is EuPathDB, a major collection of databases covering more than 170 eukaryotic pathogens and selected pathogen hosts. The latest update has dramatically expanded the range of EuPathDB’s content, which now includes protein microarray, metabolic pathways, compounds, quantitative proteomics, copy number variation, and polysomal transcriptomics (Aurrecoechea et al., 2017). Despite all these extremely useful databases, finding a promising novel candidate drug for a defined neglected disease remains a major challenge. When choosing a computational repurposing tool (or combining several), it should be possible to subsequently confirm predictions in the field through different analytic validation methods. Many of these validation methods rely on databases of true drug-indications pairs as their unique source of information, which tend to underestimate the potential of novel repurposing candidates as leads (Brown & Patel, 2017). In order to address this limitation, Brown and Patel recently developed the repoDB, a database that contains a standard set of true positives (approved drugs) and true negatives (failed drugs), which can be used to properly and reproducibly benchmark computational repurposing methods (Brown & Patel, 2017). This promising tool brings together approved indications from DrugCentral (Ursu et al., 2017) and failed ones from the Aggregate Analysis of Clinical Trials Database (McCray & Ide, 2000), which opens the door to explore exciting new paths in the field of drug repurposing that would likely be overlooked by traditional approved-drug-based approaches. Last but not least, drug repurposing approaches must try to precisely predict and explain potential side effects and adverse drug reactions (ADR). Pharmacovigilance of new side

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effects’ associations with approved drugs can be improved with computational tools, allowing analysis and deconvolution of complex data surrounding the drug’s use and effects (White, Tatonetti, Shah, Altman, & Horvitz, 2013; Yom-Tov & Gabrilovich, 2013). Drug-side effect associations are very dispersed through public information databases. In order to address this issue, Kuhn, Letunic, Jensen, and Bork (2016) created the SIDER (Side Effect Resource) database of drugs and ADRs. The current version contains data on 1430 drugs, 5880 ADRs, and 140,064 drug-ADR pairs, which provides a more detailed picture of the ways in which drugs cause adverse reactions. The Offsides database is an extremely interesting complementary resource to SIDER. Offsides contains 438,801 off-label side effects for 1332 drugs and 10,097 ADRs. Interestingly, this database covers approximately 39% of SIDER associations from adverse event reports, leading to the discovery of different associations from those reported during clinical trials before drug approval (Tatonetti, Ye, Daneshjou, & Altman, 2012).

3.2 Computational Tools For Drug Repurposing in Neglected Infectious Diseases: A Virtual Translational Reality From Computers to Clinics Computational methods have an increasing importance in the rational design of novel, economical, efficient, and personalized drugs. These processes not only guide experimental approaches, but also assist in the interpretation of their outcomes. It is worth mentioning that modern drug discovery/development is one of the areas positively impacted by the fourth industrial revolution (industry 4.0), where cyber and physical spaces are constantly connected. These integrative approaches are helping in the challenging task of drug repurposing to tackle neglected diseases. Some aspects of this reality include: personalized medicine, big data analytics and advanced algorithms, cloud computing, and the need for appropriately trained individuals. Virtual findings are supported by experimental validation whose outcome can also be predicted computationally, thus integrating solutions to improve the chemotherapy arsenal for tackling NIDs. This includes methods that can help resurrect orphan drugs (Aronson, 2006), supporting R&D focused on life-saving programs to develop products for treatment of NIDs (Villa, Compagni, & Reich, 2009). In general, computer-aided drug design (CADD) can be divided into target-based and ligand-based approaches (Issa, Kruger, Byers, & Dakshanamurthy, 2013). Structure- or target-based methods use available information from the 3D structure of the biological target (usually proteins), either experimentally solved or obtained via comparative modeling, to develop novel ligands for specific pockets or binding sites, taking into consideration the complementary features (both geometrical and physicochemical). Docking, virtual screening, and molecular dynamics simulations are examples of methods that have been applied to target-based drug design. Ligand-based drug design, on the other hand, relies on the information of the structure of a compound as a way to identify a minimum set of characteristics required for a molecule to be active/bind to the target of interest. Quantitative structure-activity relationships models (QSAR) are an example of this class of methods. In the following sections, we introduce and discuss the available computational methods that could prove useful for drug repositioning against NIDs, presenting examples of potential drug candidates discovered through ligand-based or target-based computer-assisted strategies.

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3.2.1 Ligand-Based Approaches Traditional QSAR-based methods are very common in early drug design and discovery, whether to establish new lead compounds or for use in drug repurposing. The main task is to predict biological activity—in this case, related to the expected antiinfectious disease potential—ascertained from structural features of known compounds. In this context, a library set of known drugs can have their biological activity predicted, associated with their chemical structure and based on physicochemical properties or theoretical molecular descriptors of chemicals. Once a hit (repurposed drug) is experimentally validated, the results of these assays can be used to perform more accurate QSAR analysis, repeating the workflow. A lead compound is reached when criteria such as low toxicity and potential for further modifications are met (Williams et al., 2015). This method can also be adapted to predict target affinity and identify new potential targets. QSAR-based approaches have been widely used to discover new hits against infectious diseases for drug repurposing (Gomes et al., 2017; Melo-Filho et al., 2016; Neves et al., 2016) and have also been applied to lead optimization and virtual screening (Verma, Khedkar, & Coutinho, 2010). Some examples of studies applying QSAR to identify repurposable drugs against NIDs are presented in Table 4. TABLE 4 Examples of Drug Candidates for Repurposing Against Neglected Infectious Diseases Determined by Computer-Aided Methods Drug Candidate

Originally for Treatment of

Repurposed Against

NMT inhibitors Cancer Filarial DDD85646 and Fungal infection nematodes DDD100870 Viral infection Protozoal infection

Target

Computational Method Used References

N-Myristoyltransferase Comparative (NMT, EC 2.3.1.97) homology modeling

Galvin et al. (2014)

Human PDE4 Inflammation inhibitor GSK- (inhibitors of 256066, NPD- human PDE4) 008, NPD-039

Phosphodiesterase B1 Trypanosomes (PDEs, EC 3.1.4) (African and American trypanosomiasis)a

Structureactivity relationship

Blaazer et al. (2018) and Ochiana, Bland, Settimo, Campbell, and Pollastri (2015)

Human kinase Cancer inhibitors

Trypanosomatids Cyclin-dependent (Leishmania, kinase (CDK) Trypanosomes) Casein kinase Alpha kinase

–

Reviewed by Dichiara et al. (2017)

Paroxetine

Depression

Schistosomes

Inhibition of Schistosoma Homology mansoni serotonin modeling transporters Molecular docking

Weeks et al. (2018)

Atovaquone Carvedilol

Pneumocystis Malaria Toxoplasma Leishmania (atovaquone) Congestive heart failure (carvedilol)

Helminths

Inhibition of Ascaris suum mitochondrial rhodoquinol-fumarate reductase

Uzochukwu, Olubiyi, and Akpojotor (2014)

Molecular docking Molecular dynamics simulations

Continued

2. THEORETICAL BACKGROUND AND METHODOLOGIES

TABLE 4 Examples of Drug Candidates for Repurposing Against Neglected Infectious Diseases Determined by Computer-Aided Methods—cont’d Drug Candidate

Originally for Treatment of

Ritonavir Lopinavir Nelfinavir Ivermectin

Viral infection Virus (dengue) Parasite infestation

NS3 helicase

Cinnarizine Griseofulvin Tetrabenazine Clotrimazole Aprindine

Allergies Fungal infection Psychosis Bacterial infection Arrhythmia

Voltage-dependent Target-based calcium channel chemogenic (Smp_159990.1) screening Tubulin β chain (Smp_192110.1) Vesicular amine transporter (Smp_121920.1) Ca2+-activated K+ channel (Smp_161450.1) HSP73 (Smp_106930.1) Calmodulin (Smp_134500.1)

Neves et al. (2015)

Amiodarone Bromocriptine

Cancer Typanosomes Arrhythmia Parkinson’s disease Hyperprolactinemia Type-2 diabetes

Cruzainb (E.C. 3.4.22.51)

Bellera et al. (2013) and Martinez et al. (2015)

Odanacatib (human cathepsin K inhibitor)

Postmenopause Osteoporosis

Trypanosomes

Cruzain (E.C. 3.4.22.51) Molecular modeling

Ndao et al. (2014) and Sajid, Robertson, Brinen, & McKerrow (2011)

Trypanosomes

Cruzain (E.C. 3.4.22.51) Virtual screening

Bellera et al. (2014)

Trypanosomes Triclabendazole Fungal infection Sertaconazole Parasite infestation Leishmania Paroxetine Depression

Trypanothione synthetase

Modeling Virtual screening

Alberca et al. (2016)

Budlein A

Inflammation

Trypanosomes

Unknown

QSARc

Schmidt, Da Costa, Lopes, Kaiser, and Brun (2014)

Helenalin

Inflammation Cancer

Trypanosomatids Unknown

HQSARd

Schmidt, Nour, Khalid, Kaiser, and Brun (2009)

Lysine deacetylase inhibitors

Cancer Psychosis

Trypanosomatids Lysine deacetylase Helminths (KDAC)

Homology Wang et al. modeling (2015) Ligand docking

Levothyroxine Hypothyroidism

a

Repurposed Against

Schistosomes

Target

Computational Method Used References Molecular docking Molecular dynamics simulations

Modeling Virtual screening

Reviewed by Botta, Rivara, Zuliani, & Radi (2018)

African trypanosomiasis: Sleeping sickness caused by Trypanosoma brucei (Human African trypanosomiasis—HAT) and nagana (the animal form of sleeping sickness); American trypanosomiasis: Chagas’ disease, caused by T. cruzi. b Cruzain is the recombinant version of Cruzipain (truncated at C-terminal end) (Eakin, Mills, Harth, McKerrow, & Craik, 1992). c QSAR, quantitative structure-activity relationship. d Hologram QSAR.

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Several software tools are available to perform QSAR modeling, including: QSAR and Modelling Society (http://www.qsar.org/); Cheminformatics (http://www.cheminformatics.org/) (https://chembench.mml.unc.edu/); Multiple Linear Regression-QSAR: QSARINS (www. qsar.it); Partial Least Squares-QSAR: QSAR modeling (http://lqta.iqm.unicamp.br); 3D-QSAR: Open 3D-QSAR (http://open3dqsar.sourceforge.net); 4D-QSAR-LQTA-QSAR (http://lqta.iqm.unicamp.br); and VCCLab (www.vcclab.org). Some of the aforementioned software tools do not include molecular descriptor computing modules, but many are available: Dragon (www.vcclab.org/lab/edragon); Molconn-Z (www.edusoft-lc.com/molconn); Model (http://jing.cz3.nus.edu.sg/cgi-bin/model/model.cgi); PaDEL-descritor (http://padel.nus. edu.sg/software/padeldescriptor); Marvin (www.chemaxon.com); KNIME (www.knime. org); 3D-QSAR (https://www.3d-qsar.com/); DTC Lab tools (http://teqip.jduv.ac.in/ QSAR_Tools); other tools and support: (http://bigchem.eu/sites/default/files/Online2_ Tetko.pdf); (http://bidd.nus.edu.sg/BIDD-Databases/TTD/Reference1.pdf). A set of library compounds can be used to guide ligand-based virtual screening as structures for the training and generation of pharmacophore models (to be validated in the literature). Next, results from pharmacophore modeling are applied in virtual screening and database searching. Molecular similarities methods and computational pharmacophore modeling can use existing data to model and filter chemical entities as inputs for an in vitro assay. Computational 2D similarity has been applied to predict cross-reactivity in immunoassays (Krasowski, Siam, Iyer, & Ekins, 2009), and this same strategy can be applied to search for compounds having pharmacophore-feature similarities with known drugs, supporting the idea of cross-reactive compounds; when similar structures also share biological activity. Simple similarity analysis can be applied to large, publicly available compound libraries (see Part II Section 3.1) for comparison with existing drugs. Prediction of activity spectrum for substances (PASS) is an example of a method that can reveal the repurposing potential of drugs (Poroikov, Filimonov, Borodina, Lagunin, & Kos, 2000). Using the same similarity logic, molecular docking can be applied to ligands, searching for complementary shape and electrostatic interactions with known targets (Li, An, & Jones, 2006), followed by experimental validation. Another important feature of the 2D ligand-based approach is the use of biological information (e.g., proteome) to establish relationships between biological activity spectra and structure (Fliri, Loging, Thadeio, & Volkmann, 2005). Integration of biospectra, networks, and various databases, among others, can be useful not only to identify potential repurposing drugs, but to make inferences with respect to toxicity, off-target effects, and polypharmacology. A recent approach developed at Massachussetts Institute of Technology (MIT) was the development of a synthetic library of “xenoproteins” that consist of nonnatural amino acids (the stereoisomer levo-amino acid instead of the natural dextroamino acid) that are being screened to find chemotherapy alternatives against Ebola virus (Gates et al., 2018). Another class of methods for drug repurposing involves the use of a systematic biological/ pharmacological approach to assess transcriptional data for the identification of complementary gene-expression signatures. DrugSig (Wu, Huang, Zhong, & Huang, 2017), gene2drug (Napolitano et al., 2018), and DrugDiseaseNet (Peyvandipour, Saberian, Shafi, Donato, & Draghici, 2018) are examples of such tools. Despite considerable efforts to optimize pharmacokinetic and toxicological properties (Absorption, Distribution, Metabolism, Excretion, Toxicity; ADMET) of compounds in the early stages of drug development, safety and toxicity remain the principle causes of failure during clinical trials (Waring et al., 2015). 2. THEORETICAL BACKGROUND AND METHODOLOGIES

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Computational methods capable of predicting and optimizing these properties play an important role when repurposing lead compounds. Pires and co-workers have recently developed pkCSM (Pires, Blundell, & Ascher, 2015), a comprehensive platform for assessing the pharmacokinetics and toxicological properties of small molecules. This platform uses the concept of graph-based signatures (Pires et al., 2011) to train and test predictive models via supervised learning. It is available as a user-friendly web-server capable of predicting 30 different ADMET properties. Other interesting alternatives include admetSAR (Cheng et al., 2012) and SwissADME (Daina, Michielin, & Zoete, 2017). 3.2.2 Target-Based Approaches Target-based repurposing relies on the knowledge that a plethora of given drug-like chemicals could bind a specific protein target, driving the search for new applications for known drugs. Evolutionarily conserved targets support the fact that shared features lead to common active inhibitors amongst different organisms, guiding repositioning from a drug’s original purpose to another disease (Pollastri & Campbell, 2011). The main advantage of adopting target-based methods is that the target is known, allowing virtual structure screenings by either homology modeling or X-ray crystallography, and facilitating further mechanistic experimental validations (Klug, Gelb, & Pollastri, 2016). In this regard, the known target from a given pathogen can be selectively screened, avoiding side effects on human target homologues. For this reason, unique/exclusive pathogen targets are preferable when repurposing drug candidates against NIDs. High levels of amino acid-sequence identity between pathogen and host target reduces the chances of virtually identifying a specific inhibitor. However, the structure-based drug design (SBDD) approach overcomes this concern by considering physicochemical aspects, such as kinetics and structural features. This combined knowledge helps isolate pathogen enzyme-specific inhibitors (Larson et al., 2008). The democratization of massive sequencing technologies allows one to obtain fully sequenced genomes that, combined with systematic screening of drug-like molecules, can be used in a high-throughput manner to identify lead candidates; a strategy known as chemogenomics (Andrade et al., 2018; Pollastri & Campbell, 2011). A team headed by Dr. Carolina H. Andrade (Universidade Federal de Goias, Goiania, Brazil) was able to identify six potential already-marketed drug candidates with antifungal, antiallergic, antipsychotic, antibacterial, and antiarrhythmic properties with predictive antischistosomal activity (Table 4; Neves, Braga, Bezerra, Cravo, & Andrade, 2015). This predictive result was validated when previously reported repurposed antischistosomal drugs were found using the target-based chemogenomic strategy (Neves et al., 2015). Another target-based approach considers not only the specific target, but also the target class as well. In this case, the repurposed drug can act on a plethora of homologous target classes within the infectious agent. Even when a specific target is absent, the pathogen can maintain cellular function associated with a given target class. As such, phenotypic characterization is essential to this method. To illustrate: lapatinib is an anticancer drug that acts through human EGFR (epidermal growth factor receptor) tyrosine kinase inhibition, and is repurposed as an antrypanosomal agent (Patel et al., 2013). However, trypanosomatids do not possess any tyrosine kinase receptors (Naula, Parsons, & Mottram, 2005), although there is evidence of tyrosine phosphorylation. Imatinib, an anticancer drug used to treat chronic myelogenous and acute lymphocytic leukemia, acts by inhibiting Bcr-Abl tyrosine kinase,

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but can also stop Leishmania sp. proliferation in culture and stimulate CRK3 (cyclin dependent serine/threonine kinase, essential for normal cell cycle progression) expression (Rubens do Monte-Neto, personal communication). Thus, even though the mammalian target for lapatinib and imatinib is absent in Trypanosoma sp. and Leishmania sp., respectively, they are active through a target class yet to be described. A given therapeutic target can also be studied based on computational simulations, taking into consideration the physicochemical properties of atoms/molecules on molecular dynamics. One must take into account the idea of a system in constant dynamic evolution with interacting particles, bearing in mind their forces and potential energies. As such, structural insight can contribute to guide drug repurposing in a live, dynamic system aided by computational simulations. For example, molecular dynamics simulations have been applied to pinpoint an RNA-editing ligase of Trypanosoma brucei (TbREL1), an essential protein for parasite survival—and a promising target for structure-based drug design (Amaro, Swift, & McCammon, 2007). It is also worth noting that one must consider the in vivo system as an aqueous solvation and include free energies from ions and water in simulations. For example, Hoelz et al. (2016) brought insight on Nequimed176 (NEQ176)’s inhibition of cruzain, which, in aqueous solvent at pH 5.5, adopts a closed conformation in the presence of an inhibitor and when influenced by hydrogen-bonding interactions. Cruzain, the recomabinant version of cruzipain, is one of the main therapeutic targets from Trypanosoma cruzi considered for drug repurposing (Table 4). The wealth of structural information accumulated over the years, as well as advances in comparative homology modeling, have enabled the elaboration of computational methods to assist the drug development process. These methods have helped elucidate mechanisms of binding and action of drugs, as is demonstrated in the work of Dror et al. (2011) on GPCR drugs via molecular dynamics. These methods have also helped in the further understanding of the molecular effects of mutations leading to resistance (Phelan et al., 2016). When a potential target of interest lacks an experimentally solved structure, comparative modeling can be used if the structure of a homologue is known. The two most widely used tools are Modeller (Sali & Blundell, 1993), developed and maintained by Andrej Sali, and SWISS-MODEL (Arnold, Bordoli, Kopp, & Schwede, 2006), a web-based alternative that not only permits the modeling process (including the search for homologues with known structures), but also encompasses a proteomic scale repository of homology models (over 1.4 million) for different organisms. Once a structure is available (either experimentally, or modeled via comparative modeling), identifying druggable (Volkamer, Kuhn, Rippmann, & Rarey, 2012) sites or pockets is an important step prior to performing structure-based virtual screening for hit identification. A widely used open-source tool for pocket detection is Fpocket (Le Guilloux, Schmidtke, & Tuffery, 2009). Fpocket’s method is based on clustering vertices from Voronoi tessellations and can be run on a large scale. It also provides feature characterization and ranking of pockets. An interesting alternative is Ghecom (Kawabata, 2010), a web-based, grid-based method that identifies pockets by placing probe spheres of different radii on protein surfaces and defining the pocket as a “space into which a small spherical probe can enter, but a large probe cannot” (Kawabata, 2010). In this way, the tool not only defines the pocket region, but also characterizes it by depth, a feature that can be used for prioritization.

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Docking is one of the most common computational techniques for structure-based virtual screening of compounds. Given a protein pocket (usually considered a rigid body) and a compound (with its rotatable bonds), docking aims to identify the preferred compound pose (position and orientation) that optimizes interactions to form a stable complex. The two main components of docking algorithms are (1) a search algorithm that tests possible conformations, and (2) a scoring function that evaluates and ranks the optimal poses. Recent efforts have been focused on proposing new and better scoring functions (Pires & Ascher, 2016; Wojcikowski, Ballester, & Siedlecki, 2017). Several docking methods are freely available and allow for automated screening of compounds. Web-based services for protein-ligand docking include SwissDock (Grosdidier, Zoete, & Michielin, 2011), DockingServer (Bikadi & Hazai, 2009), and DOCK Blaster (Irwin et al., 2009), while more expert systems that allow for advanced parametrization include, amongst others, rDock (Ruiz-Carmona et al., 2014), EADock (Grosdidier, Zoete, & Michielin, 2007), and, the most widely used, Autodock Vina (Trott & Olson, 2010). Machine learning-based methods are a scalable alternative to docking for identification of lead compounds. They are usually based on extracting features from protein pockets to predict which ligands are most likely to bind. These could range from small molecules (Pires, de Melo-Minardi, da Silveira, Campos, & Meira Jr., 2013) to fragments (Tang & Altman, 2014). Another important aspect during drug development is predicting effects of mutations on protein-small molecule affinity as a means of understanding and anticipating drug resistance. Aside from computationally intensive methods, such as molecular dynamics, a web-based approach, mCSM-lig (Pires, Blundell, & Ascher, 2016), is capable of quantitatively predicting effects of missense mutations in protein-ligand affinity complexes, aiding in the identification of potential resistance hot-spots in protein pockets, which could then be preemptively avoided during hit optimization.

3.3 Integration of Databases and Computational Tools for Drug Repurposing in Neglected Infectious Diseases Lara-Ramirez et al. (2017) in a recent work have applied a computational drug repositioning method based on molecular docking to identify new inhibitors for the Trypanosoma cruzi trans-sialidase. A structure-based virtual screening using Autodock Vina was performed for 3180 FDA-approved drugs that were collected from the ZINC database. The compounds with best poses were analyzed regarding their physicochemical properties and most of them complied with Lipinkski’s rule of five. From this pool, seven compounds were selected for experimental validation in vitro and in vivo and four drugs showed trypanocidal effects in the range of 75%–100%, showing how integration of computational resources (databases and tools) can effectively assist drug repositioning in NIDs.

4 PERSPECTIVES AND CONCLUDING REMARKS Massive efforts are still based on direct in vitro, FDA-approved drug screenings (Ekins et al., 2011; Zheng et al., 2018); however, rational computer-aided methods must be included

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in the drug-discovery pipeline for NIDs. There is no reason to invest in trial-and-error methods without prior computational insight. We understand that specialized human resources represent a bottleneck in this field, and computer scientists should be endorsed. Although computer-assisted methods followed by experimental validation sounds like a logical pathway in drug discovery and development (DDD), this workflow is less frequent than direct in vitro drug screening without previous computational analysis—evidence that computer scientists and a multidisciplinary team are necessary to accelerate the drug repositioning pipeline. Predictive computational methods are essential to increase success rates at the experimental validation point. Collaborative initiatives must be supported to bring together efforts from academia, research institutes, and the pharmaceutical industry, and to stimulate private and governmental translational programs aimed at funding solutions for more effective treatments. For obvious reasons many CADD studies focused on drug repurposing are dedicated to Chagas disease, sleeping sickness, schistosomiasis, and leishmaniasis, but little or no attention is dedicated to diseases such as dracunculiasis, fascioliasis, yaws, echinococcosis or river blindness, thus neglecting the neglected. Efforts are still needed to cover, at least computationally, a wide spectrum of NIDs and unearth the lead compounds to be experimentally validated. Among the CADD methods, virtual screening, QSAR (ligand-based), and molecular dynamics simulations (target-based) are broadly adopted as the main strategies to guide drug repurposing against NIDs. Predictive ADMET or the combination of different approaches, including in-house strategies, are not common for already-marketed drugs. This differs when testing new small molecule compound libraries. Many studies in medicinal chemistry have resulted in innovative computational solutions to identify novel uses for old drugs. These types of solutions should be encouraged, and a computer-aided repurposing pipeline must be supported not only by academics, but also by policy-makers and public health programs. Closing this chapter, it is worth highlighting that, for all infectious diseases, drug development is an intricate process rather than the linear pipeline often pictured (Baxter et al., 2013). Drug repurposing provides “shortcuts” in the process, because: (1) we can work on previously known “druggable” targets; and (2) we can rely on massive amounts of already available high-quality data that can be used and presented to the regulatory authorities (Ekins et al., 2011). Consequently, the overall R&D process of bringing a new drug to market becomes more time- and cost-effective when compared to traditional de novo drug discovery pipelines (Fig. 2). Several examples for NIDs have been described in this chapter, including compounds with leishmanicidal, antitrypanosomal, or anti-Chagas disease activity. However, despite that, drug repurposing potentially provides faster and cheaper drug-discovery pipelines (especially for NIDs where time, resources, and information are scarce), the whole process is limited by the fact that the drug must be capable of repositioning against a precise NID, which is not always possible. Consequently, drug repurposing and the de novo development of novel drugs must be considered two independent but complementary approaches to achieve novel and effective therapeutic agents against NIDs. This is especially important for pharmaceutical companies beginning to realize that repositioning can effectively extend the market for a compound (additional commercial value) and bring novel applications for orphan and shelved compounds at a very interesting level of financial risk. In fact, as the concept of market is

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FIG. 2

A comparison of traditional de novo drug discovery and development versus drug repurposing. The de novo drug discovery and development process is likely to last at least 10–17 years from the initial idea to a marketed product (thick-line path). The probability of success is lower than 10%. Drug repositioning has many benefits, mainly lower cost and a shorter time before marketing the drug (thin-line path). Repurposing approved drugs helps avoid problems during clinical trials, such as drug toxicity or unfavorable pharmacokinetics.

essential for the companies producing drugs, different governmental agencies have tried to find and implement various vehicles to increase the interest of pharmaceutical companies in working on drug repurposing for NIDs. Tax credits and voucher schemes have been attempted as incentives in recent years (Croft, 2016). However, a voucher-triggered review aiming to detect possible pitfalls found little evidence that vouchers for NIDs were achieving their public health aims (Mullard, 2015). Additionally, in a recently published paper, Prof. Simon Croft, first R&D Director of DNDi (from 2008 to 2014), pointed to two major aspects that should not be forgotten when addressing the problem of drug development/ repurposing in NIDs: the need to both generate high-quality data in many endemic countries and effectively increase the engagement of endemic countries in the R&D process (Croft, 2016). MDA programs have been proposed as a solution to tackle NIDs [e.g., MDA for schistosomiasis (Wang & Liang, 2015)]. However, the MDA approach is controversial as it risks exacerbating the already-prevalent problem of drug/multidrug resistance observed for many pathogens. Particularly in the NIDs domain there is a worrying increase in the number of drug/multidrug-resistant strains, which urges the rapid identification and marketing of novel therapeutic agents, thus hindering the implementation of effective MDA programs. A difficult but refined option to slow the potential spread of drug resistance through

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MDA would be the implementation of mass screening and treatment (MSAT) approaches, whereby drugs are administered only to NID-diagnosed individuals. Nonetheless, to achieve durable MSAT we require effective, affordable drugs against both wild-type and drugresistant strains, in addition to better advocacy coupled with enhanced scientific and public health programs. Consequently, the issue of drug resistance presents new opportunities and challenges in terms of drug repurposing.

Acknowledgments Authors would like to thank Victoria Wagner for her assistance in editing the manuscript. C. Ferna´ndez-Prada is supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (RGPIN-2017-04480).

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