- Email: [email protected]
I6 Natural product-based protein amyloid inhibitors
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Abstracts / Biochemical Pharmacology 139 (2017) 105–110
intervention studies imply that intake of quercetin-rich onion improves vascular health. Onion may be superior to quercetin supplement from the viewpoint of quercetin bioavailability, probably because the food matrix enhances the intestinal absorption of quercetin. a-Glucosylation increases its bioavailability by elevating the accessibility to the absorptive cells. Prenylaton may enhance bioaccumulation at the target site by increasing the cellular uptake. However, these chemical modifications do not guarantee health benefits to the vascular system. Although dietary quercetin is exclusively present as their conjugated form in the blood stream, its vascular function seems to be mediated by inflammation-dependent deconjugation reaction. Finally, bioavailability of non-absorptive polyphenols to microbiota in the gut should be pointed out, as the colonic microbiota is regarded as a separate organ within the human host. doi:10.1016/j.bcp.2017.06.051
I5 Bioavailability and anti-diabetic action of naturally-occurring flavonoids and phenolic acids Gary Williamson School of Food Science and Nutrition, University of Leeds, Leeds, UK Flavonoids and phenolic acids (polyphenols) are naturallyoccurring bioactive compounds from plants, often found in high amounts in many foods and beverages. They are also present in many plant based dietary supplements, at levels up to pharmaceutical doses. The pathways of absorption and metabolism of the most common dietary polyphenols are now mostly understood. The enzymes involved, their site of action, essential transporters and exact conjugating enzymes have been characterised, and in vitro mechanistic experiments have been supported by numerous studies, using healthy volunteers, ileostomists, intestinal perfusion, and animal models. Since the types of metabolites in blood have been identified and some synthesised, we can more carefully design in vitro experiments and translate the findings into human intervention studies. The long-term health risks of excess dietary sugar consumption remains a controversial topic in nutrition. Some of the deleterious effects of dietary sugar have been linked to high blood glucose ‘‘spikes” following a meal or beverage, which are more extreme and uncontrollable in subjects with metabolic syndrome. Certain dietary polyphenols attenuate blood glucose after a high carbohydrate meal, and in addition, the absorbed polyphenols also help to repair or prevent the damage cause by high glucose. The combination of effects is essential for the overall action of dietary polyphenols where the consequence is maintenance of normal body metabolism and reduction in the risk of developing type 2 diabetes. doi:10.1016/j.bcp.2017.06.052
peutic strategy is to discover and develop protein amyloid inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. Using amyloidogenic proteins amylin, amyloid beta-peptide, and tau as model systems, we screened libraries of natural compounds used in Complementary and Alternative Medicine. We identified multiple potent inhibitors, including rosmarinic acid and baicalein (200 nM and 1 lM respectively in apparent IC50 Þ [1]. These compounds disaggregate amyloidogenic protein fibrils, significantly reduce protein amyloidinduced cytotoxicity and toxic amyloid oligomers in circulating sera and/or cerebrospinal fluid from diseased animal models. Dissecting the functional groups of these compounds, we demonstrated, for the first time to our knowledge, that the vicinal hydroxyl groups of the catechol groups played key functional roles in amyloid inhibition in more than two dozen catechol-containing compounds, including many plant- and fruit-derived flavonoids and other phenolic compounds [2]. Compounds with multiple catechol groups, such as rosmarinic acid, exhibited additive effects. We provided further mass spectrometric evidence that incubating several of these catecholcontaining inhibitors with amyloidogenic proteins leads to covalent adducts consistent with Schiff base conjugation mechanism to interfere with toxic amyloid formation. Consistent with forming covalent adducts via the mechanism of quinone intermediates, we demonstrated that many catechol-containing natural products significantly increase amyloid inhibition effects under autooxidation or oxidizing conditions. Lastly, I will discuss our approach to enhance certain natural product solubility/bioavailability by engineering natural compound-incorporating nanoparticles [3]. Acknowledgement: This work is in part supported by Virginia Tech new faculty start-up funds, Commonwealth Health Research Board (CHRB), Alzheimer’s and Related Diseases Research Award Fund (ARDRAF) from Virginia Center on Aging, Diabetes Action Research and Education Foundation (DAREF), and Virginia Tech Center for Drug Discovery (VTCDD). References [1] P. Velander et al., Biochemistry 55 (2016) 4255–4258. [2] L.Wu, et al. Rosmarinic acid, a catechol-containing natural product, is a potent inhibitor of amylin amyloidosis. Submitted, 2017. [3] P. Velander et al., Biochem. Pharmacol. (2017) [Epub ahead of print]. doi:10.1016/j.bcp.2017.06.053
Theme 3: Translating novel pathways and mechanisms of action into the clinical use of nutraceuticals and natural product pharmaceuticals
I6 Natural product-based protein amyloid inhibitors Bin Xu Department of Biochemistry and Center for Drug Discovery, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, United States
I8 Marine natural products as starting points for drug discovery and development Hendrik Luesch Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USA, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, USA E-mail address: [email protected]
Toxic protein amyloid formation has been implicated in more than a dozen protein misfolding diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. Currently there are no effective disease-modifying drugs available. One common thera-
Natural products from marine cyanobacteria cover therapeutically relevant chemical space. This is underscored by the approval of brentuximab vedotin, an antibody-drug conjugate with a cytotoxic payload that is derived from dolastatin 10 which is produced
Abstracts / Biochemical Pharmacology 139 (2017) 105–110
intervention studies imply that intake of quercetin-rich onion improves vascular health. Onion may be superior to quercetin supplement from the viewpoint of quercetin bioavailability, probably because the food matrix enhances the intestinal absorption of quercetin. a-Glucosylation increases its bioavailability by elevating the accessibility to the absorptive cells. Prenylaton may enhance bioaccumulation at the target site by increasing the cellular uptake. However, these chemical modifications do not guarantee health benefits to the vascular system. Although dietary quercetin is exclusively present as their conjugated form in the blood stream, its vascular function seems to be mediated by inflammation-dependent deconjugation reaction. Finally, bioavailability of non-absorptive polyphenols to microbiota in the gut should be pointed out, as the colonic microbiota is regarded as a separate organ within the human host. doi:10.1016/j.bcp.2017.06.051
I5 Bioavailability and anti-diabetic action of naturally-occurring flavonoids and phenolic acids Gary Williamson School of Food Science and Nutrition, University of Leeds, Leeds, UK Flavonoids and phenolic acids (polyphenols) are naturallyoccurring bioactive compounds from plants, often found in high amounts in many foods and beverages. They are also present in many plant based dietary supplements, at levels up to pharmaceutical doses. The pathways of absorption and metabolism of the most common dietary polyphenols are now mostly understood. The enzymes involved, their site of action, essential transporters and exact conjugating enzymes have been characterised, and in vitro mechanistic experiments have been supported by numerous studies, using healthy volunteers, ileostomists, intestinal perfusion, and animal models. Since the types of metabolites in blood have been identified and some synthesised, we can more carefully design in vitro experiments and translate the findings into human intervention studies. The long-term health risks of excess dietary sugar consumption remains a controversial topic in nutrition. Some of the deleterious effects of dietary sugar have been linked to high blood glucose ‘‘spikes” following a meal or beverage, which are more extreme and uncontrollable in subjects with metabolic syndrome. Certain dietary polyphenols attenuate blood glucose after a high carbohydrate meal, and in addition, the absorbed polyphenols also help to repair or prevent the damage cause by high glucose. The combination of effects is essential for the overall action of dietary polyphenols where the consequence is maintenance of normal body metabolism and reduction in the risk of developing type 2 diabetes. doi:10.1016/j.bcp.2017.06.052
peutic strategy is to discover and develop protein amyloid inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. Using amyloidogenic proteins amylin, amyloid beta-peptide, and tau as model systems, we screened libraries of natural compounds used in Complementary and Alternative Medicine. We identified multiple potent inhibitors, including rosmarinic acid and baicalein (200 nM and 1 lM respectively in apparent IC50 Þ [1]. These compounds disaggregate amyloidogenic protein fibrils, significantly reduce protein amyloidinduced cytotoxicity and toxic amyloid oligomers in circulating sera and/or cerebrospinal fluid from diseased animal models. Dissecting the functional groups of these compounds, we demonstrated, for the first time to our knowledge, that the vicinal hydroxyl groups of the catechol groups played key functional roles in amyloid inhibition in more than two dozen catechol-containing compounds, including many plant- and fruit-derived flavonoids and other phenolic compounds [2]. Compounds with multiple catechol groups, such as rosmarinic acid, exhibited additive effects. We provided further mass spectrometric evidence that incubating several of these catecholcontaining inhibitors with amyloidogenic proteins leads to covalent adducts consistent with Schiff base conjugation mechanism to interfere with toxic amyloid formation. Consistent with forming covalent adducts via the mechanism of quinone intermediates, we demonstrated that many catechol-containing natural products significantly increase amyloid inhibition effects under autooxidation or oxidizing conditions. Lastly, I will discuss our approach to enhance certain natural product solubility/bioavailability by engineering natural compound-incorporating nanoparticles [3]. Acknowledgement: This work is in part supported by Virginia Tech new faculty start-up funds, Commonwealth Health Research Board (CHRB), Alzheimer’s and Related Diseases Research Award Fund (ARDRAF) from Virginia Center on Aging, Diabetes Action Research and Education Foundation (DAREF), and Virginia Tech Center for Drug Discovery (VTCDD). References [1] P. Velander et al., Biochemistry 55 (2016) 4255–4258. [2] L.Wu, et al. Rosmarinic acid, a catechol-containing natural product, is a potent inhibitor of amylin amyloidosis. Submitted, 2017. [3] P. Velander et al., Biochem. Pharmacol. (2017) [Epub ahead of print]. doi:10.1016/j.bcp.2017.06.053
Theme 3: Translating novel pathways and mechanisms of action into the clinical use of nutraceuticals and natural product pharmaceuticals
I6 Natural product-based protein amyloid inhibitors Bin Xu Department of Biochemistry and Center for Drug Discovery, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, United States
I8 Marine natural products as starting points for drug discovery and development Hendrik Luesch Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USA, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, USA E-mail address: [email protected]
Toxic protein amyloid formation has been implicated in more than a dozen protein misfolding diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. Currently there are no effective disease-modifying drugs available. One common thera-
Natural products from marine cyanobacteria cover therapeutically relevant chemical space. This is underscored by the approval of brentuximab vedotin, an antibody-drug conjugate with a cytotoxic payload that is derived from dolastatin 10 which is produced