Computational and Experimental Approaches to Design Inhibitors of Amylin Aggregation

Ammu    Prasanna    Kumar; Sungmun       Lee; Suryani       Lukman
Abstract

Amylin is a neuroendocrine peptide hormone secreted by pancreatic ß-cells; however, amylin is toxic to ß-cells when it is aggregated in type 2 diabetes mellitus (T2DM). It is important to understand amylin’s structures and aggregation mechanism for the discovery and design of effective drugs to inhibit amylin aggregation. In this review, we investigated experimental and computational studies on amylin structures and inhibitors. Our review provides some novel insights into amylin, particularly for the design of its aggregation inhibitors to treat T2DM. We detailed the potential inhibitors that have been studied hitherto and highlighted the neglected need to consider different amylin attributes that depend on the presence/absence of physiologically relevant conditions, such as membranes. These conditions and the experimental methods can greatly influence the results of studies on amylininhibitor complexes. Text-mining over 3,000 amylin-related PubMed abstracts suggests the combined therapeutic potential of amylin with leptin and glucagon-like peptide-1, which are two key hormones in obesity. The results also suggest that targeting amylin aggregation can contribute to therapeutic efforts for Alzheimer’s disease (AD). Therefore, we have also reviewed the role of amylin in other conditions including obesity and AD. Finally, we provided insights for designing inhibitors of different types (small molecules, proteins, peptides/mimetics, metal ions) to inhibit amylin aggregation.
Keywords: Amylin, islet amyloid polypeptide, IAPP, aggregation inhibitors, type 2 diabetes therapy, Alzheimer's disease therapy, conformation of amylin, literature review.
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Graphical Abstract

[1] 
Mukherjee A, Morales-Scheihing D, Butler PC, Soto C. Type 2 diabetes as a protein misfolding disease. Trends Mol Med  2015; 21(7): 439-49.
[http://dx.doi.org/10.1016/j.molmed.2015.04.005] [PMID:  25998900] 
[2] 
Abedini A, Schmidt AM. Mechanisms of islet amyloidosis toxicity in type 2 diabetes. FEBS Lett  2013; 587(8): 1119-27.
[http://dx.doi.org/10.1016/j.febslet.2013.01.017] [PMID:  23337872] 
[3] 
Lansbury PT Jr. Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease Proc Natl Acad Sci U S A   96(7): 3342-4. 1999
[http://dx.doi.org/10.1073/pnas.96.7.3342] 
[4] 
Sipe JD, Cohen AS. Amyloidosis. Crit Rev Clin Lab Sci  1994; 31(4): 325-54.
[http://dx.doi.org/10.3109/10408369409084679] [PMID:  7888076] 
[5] 
Sipe JD. Amyloidosis. Annu Rev Biochem  1992; 61(1): 947-75.
[http://dx.doi.org/10.1146/annurev.bi.61.070192.004503] [PMID:  1497327] 
[6] 
Taubes G. Misfolding the way to disease. Science  1996; 271(5255): 1493-5.
[http://dx.doi.org/10.1126/science.271.5255.1493] [PMID:  8599100] 
[7] 
Serpell LC. Alzheimer’s amyloid fibrils: structure and assembly Biochim Biophys Acta - Mol Basis Dis  1502(1): 16-30. 2000
[8] 
Smith DP, Jones S, Serpell LC, Sunde M, Radford SE. a systematic
	investigation into the effect of protein destabilisation on beta 2-
	microglobulin amyloid formation. J Mol Biol Academic Press  330(5): 943-54. 2003
[9] 
Serpell LC, Berriman J, Jakes R, Goedert M, Crowther RA. Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci USA  2000; 97(9): 4897-902.
[http://dx.doi.org/10.1073/pnas.97.9.4897] [PMID:  10781096] 
[10] 
Jansen R, Grudzielanek S, Dzwolak W, Winter R. High pressure promotes circularly shaped insulin amyloid. J Mol Biol  2004; 338(2): 203-6.
[http://dx.doi.org/10.1016/j.jmb.2004.02.056] [PMID:  15066425] 
[11] 
Petkova AT, Ishii Y, Balbach JJ, et al. A structural model for Alzheimer’s beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci USA  2002; 99(26): 16742-7.
[http://dx.doi.org/10.1073/pnas.262663499] [PMID:  12481027] 
[12] 
Thompson LK. Unraveling the secrets of Alzheimer’s beta-amyloid fibrils Proc Natl Acad Sci USA  100(2): 383-5. 2003
[13] 
User S. http://www.diabetesatlas.org/across-the-globe.html
[14] 
Reusch JEB, Manson JE. Management of Type 2 Diabetes in 2017: Getting to Goal. JAMA  2017; 317(10): 1015-6.
[http://dx.doi.org/10.1001/jama.2017.0241] [PMID:  28249081] 
[15] 
Wilmot E, Idris I. Early onset type 2 diabetes: risk factors, clinical impact and management. Ther Adv Chronic Dis  2014; 5(6): 234-44.
[http://dx.doi.org/10.1177/2040622314548679] [PMID:  25364491] 
[16] 
Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M. Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. Diabetes Care  2004; 27(7): 1798-811.
[http://dx.doi.org/10.2337/diacare.27.7.1798] [PMID:  15220270] 
[17] 
Stridsberg M, Wilander E. Islet amyloid polypeptide (IAPP). A short review. Acta Oncol  1991; 30(4): 451-6.
[http://dx.doi.org/10.3109/02841869109092400] [PMID:  1854502] 
[18] 
Akter R, Cao P, Noor H, et al. Islet amyloid polypeptide: structure, function, and pathophysiology. J Diabetes Res  2016; 20162798269
[http://dx.doi.org/10.1155/2016/2798269] [PMID:  26649319] 
[19] 
Caillon L, Hoffmann ARF, Botz A, Khemtemourian L. Molecular structure, membrane interactions, and toxicity of the islet amyloid polypeptide in type 2 diabetes mellitus. J Diabetes Res 2016.20165639875
[http://dx.doi.org/10.1155/2016/5639875] [PMID:  26636105] 
[20] 
Obasse I, Taylor M, Fullwood NJ, Allsop D. Development of proteolytically stable N-methylated peptide inhibitors of aggregation of the amylin peptide implicated in type 2 diabetes. Interface Focus  2017; 7(6)20160127
[http://dx.doi.org/10.1098/rsfs.2016.0127] [PMID:  29147551] 
[21] 
Lutz TA. Pancreatic amylin as a centrally acting satiating hormone. Curr Drug Targets  2005; 6(2): 181-9.
[http://dx.doi.org/10.2174/1389450053174596] [PMID:  15777188] 
[22] 
Roberson SW. 2013.https://digitalcommons.lmu.edu/ulra/awards/2013/1/
[23] 
Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev  2015; 67(3): 564-600.
[http://dx.doi.org/10.1124/pr.115.010629] [PMID:  26071095] 
[24] 
Haataja L, Gurlo T, Huang CJ, Butler PC. Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev  2008; 29(3): 303-16.
[http://dx.doi.org/10.1210/er.2007-0037] [PMID:  18314421] 
[25] 
Kiriyama Y, Nochi H. Role and cytotoxicity of amylin and protection of pancreatic islet β-cells from amylin cytotoxicity  Cells Multidisciplinary Digital Publishing Institute (MDPI) 7(8) . 2018.
[http://dx.doi.org/10.3390/cells7080095] 
[26] 
Westermark GT, Westermark P. Islet amyloid polypeptide and diabetes. Curr Protein Pept Sci  2013; 14(4): 330-7.
[http://dx.doi.org/10.2174/13892037113149990050] [PMID:  23745697] 
[27] 
Ly H, Despa F. Hyperamylinemia as a risk factor for accelerated cognitive decline in diabetes. Expert Rev Proteomics  2015; 12(6): 575-7.
[http://dx.doi.org/10.1586/14789450.2015.1104251] [PMID:  26503000] 
[28] 
Lukman S, Al Safar H, Lee SM, Sim K. Harnessing Structural Data of Insulin and Insulin Receptor for Therapeutic Designs. J Endocrinol Metab  2015; 5(5): 273-83.
[http://dx.doi.org/10.14740/jem302w] 
[29] 
Luca S, Yau W-M, Leapman R, Tycko R. Peptide conformation and supramolecular organization in amylin fibrils: constraints from solid-state NMR. Biochemistry  2007; 46(47): 13505-22.
[http://dx.doi.org/10.1021/bi701427q] [PMID:  17979302] 
[30] 
Heise H, Hoyer W, Becker S, Andronesi OC, Riedel D, Baldus M. Molecular-level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein fibrils studied by solid-state NMR. Proc Natl Acad Sci USA  2005; 102(44): 15871-6.
[http://dx.doi.org/10.1073/pnas.0506109102] [PMID:  16247008] 
[31] 
Lührs T, Ritter C, Adrian M, et al. 3D structure of Alzheimer’s amyloid-beta(1-42) fibrils. Proc Natl Acad Sci USA  2005; 102(48): 17342-7.
[http://dx.doi.org/10.1073/pnas.0506723102] [PMID:  16293696] 
[32] 
Vilar M, Chou H-T, Lührs T, et al. The fold of alpha-synuclein fibrils. Proc Natl Acad Sci USA  2008; 105(25): 8637-42.
[http://dx.doi.org/10.1073/pnas.0712179105] [PMID:  18550842] 
[33] 
Nanga RPR, Brender JR, Vivekanandan S, Ramamoorthy A. Structure and membrane orientation of IAPP in its natively amidated form at physiological pH in a membrane environment. Biochim Biophys Acta  2011; 1808(10): 2337-42.
[http://dx.doi.org/10.1016/j.bbamem.2011.06.012] [PMID:  21723249] 
[34] 
Dupuis NF, Wu C, Shea J-E, Bowers MT. Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor. J Am Chem Soc  2009; 131(51): 18283-92.
[http://dx.doi.org/10.1021/ja903814q] [PMID:  19950949] 
[35] 
Dupuis NF, Wu C, Shea J-E, Bowers MT. The amyloid formation mechanism in human IAPP: dimers have β-strand monomer-monomer interfaces. J Am Chem Soc  2011; 133(19): 7240-3.
[http://dx.doi.org/10.1021/ja1081537] [PMID:  21517093] 
[36] 
Reddy AS, Wang L, Singh S, et al. Stable and metastable states of human amylin in solution. Biophys J  2010; 99(7): 2208-16.
[http://dx.doi.org/10.1016/j.bpj.2010.07.014] [PMID:  20923655] 
[37] 
Rodriguez Camargo DC, Korshavn KJ, Jussupow A, et al. Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate. eLife  2017; 6(Nov): 6.
[http://dx.doi.org/10.7554/eLife.31226] [PMID:  29148426] 
[38] 
Mirecka EA, Feuerstein S, Gremer L, et al. β-Hairpin of islet amyloid polypeptide bound to an aggregation inhibitor. Sci Rep  2016; 6: 33474.
[http://dx.doi.org/10.1038/srep33474] [PMID:  27641459] 
[39] 
Rawat A, Maity BK, Chandra B, Maiti S. Aggregation-induced
	conformation changes dictate islet amyloid polypeptide (IAPP)
	membrane affinity. Biochim Biophys Acta Biomembr  2018.S0005-2736(18)30107-X. 
[http://dx.doi.org/10.1016/j.bbamem.2018.03.027] [PMID:  29626442] 
[40] 
Tomasello MF, Sinopoli A, Pappalardo G. On the environmental factors affecting the structural and cytotoxic properties of iapp peptides. J Diabetes Res  2015; 2015918573
[http://dx.doi.org/10.1155/2015/918573] [PMID:  26582441] 
[41] 
Jeong HR, An SSA. Causative factors for formation of toxic islet amyloid polypeptide oligomer in type 2 diabetes mellitus. Clin Interv Aging  2015; 10: 1873-9.
[PMID:  26604727] 
[42] 
Souillac PO, Uversky VN, Millett IS, Khurana R, Doniach S, Fink AL. Elucidation of the molecular mechanism during the early events in immunoglobulin light chain amyloid fibrillation. Evidence for an off-pathway oligomer at acidic pH. J Biol Chem  2002; 277(15): 12666-79.
[http://dx.doi.org/10.1074/jbc.M109229200] [PMID:  11815604] 
[43] 
Gorman PM, Chakrabartty A. Alzheimer β-amyloid peptides: structures of amyloid fibrils and alternate aggregation products. Biopolymers  2001; 60(5): 381-94.
[http://dx.doi.org/10.1002/1097-0282(2001)60:5<381:AID-BIP10173>3.0.CO;2-U] [PMID:  12115148] 
[44] 
Murphy RM. Peptide aggregation in neurodegenerative disease. Annu Rev Biomed Eng  2002; 4(1): 155-74.
[http://dx.doi.org/10.1146/annurev.bioeng.4.092801.094202] [PMID:  12117755] 
[45] 
Pallitto MM, Murphy RM. A mathematical model of the kinetics of beta-amyloid fibril growth from the denatured state. Biophys J  2001; 81(3): 1805-22.
[http://dx.doi.org/10.1016/S0006-3495(01)75831-6] [PMID:  11509390] 
[46] 
Jarrett JT, Berger EP, Lansbury PT Jr. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry  1993; 32(18): 4693-7.
[http://dx.doi.org/10.1021/bi00069a001] [PMID:  8490014] 
[47] 
Biancalana M, Koide S. Molecular mechanism of Thioflavin-T binding to amyloid fibrils. Biochim Biophys Acta  2010; 1804(7): 1405-12.
[http://dx.doi.org/10.1016/j.bbapap.2010.04.001] [PMID:  20399286] 
[48] 
Tomski SJ, Murphy RM. Kinetics of aggregation of synthetic beta-amyloid peptide. Arch Biochem Biophys  1992; 294(2): 630-8.
[http://dx.doi.org/10.1016/0003-9861(92)90735-F] [PMID:  1567217] 
[49] 
Inouye H, Kirschner DA. Polypeptide chain folding in the hydrophobic
	core of hamster scrapie prion: analysis by x-ray diffraction.
	J Struct Biol Academic Press 122(1–2): 247-55. 1998
[50] 
Brender JR, Lee EL, Cavitt MA, Gafni A, Steel DG, Ramamoorthy A. Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide. J Am Chem Soc  2008; 130(20): 6424-9.
[http://dx.doi.org/10.1021/ja710484d] [PMID:  18444645] 
[51] 
Ritzel RA, Meier JJ, Lin C-Y, Veldhuis JD, Butler PC. Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets. Diabetes  2007; 56(1): 65-71.
[http://dx.doi.org/10.2337/db06-0734] [PMID:  17192466] 
[52] 
Green JD, Goldsbury C, Kistler J, Cooper GJS, Aebi U. Human amylin oligomer growth and fibril elongation define two distinct phases in amyloid formation. J Biol Chem  2004; 279(13): 12206-12.
[http://dx.doi.org/10.1074/jbc.M312452200] [PMID:  14704152] 
[53] 
Pannuzzo M, Raudino A, Milardi D, La Rosa C, Karttunen M. α-helical structures drive early stages of self-assembly of amyloidogenic amyloid polypeptide aggregate formation in membranes. Sci Rep  2013; 3: 2781.
[http://dx.doi.org/10.1038/srep02781] [PMID:  24071712] 
[54] 
Magzoub M, Miranker AD. Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide. FASEB J  2012; 26(3): 1228-38.
[http://dx.doi.org/10.1096/fj.11-194613] [PMID:  22183778] 
[55] 
Engel MFM, Yigittop H, Elgersma RC, et al. Islet amyloid polypeptide inserts into phospholipid monolayers as monomer. J Mol Biol  2006; 356(3): 783-9.
[http://dx.doi.org/10.1016/j.jmb.2005.12.020] [PMID:  16403520] 
[56] 
Mazor Y, Gilead S, Benhar I, Gazit E. Identification and characterization of a novel molecular-recognition and self-assembly domain within the islet amyloid polypeptide. J Mol Biol  2002; 322(5): 1013-24.
[http://dx.doi.org/10.1016/S0022-2836(02)00887-2] [PMID:  12367525] 
[57] 
Nanga RPR, Brender JR, Xu J, Veglia G, Ramamoorthy A. Structures of rat and human islet amyloid polypeptide IAPP(1-19) in micelles by NMR spectroscopy. Biochemistry  2008; 47(48): 12689-97.
[http://dx.doi.org/10.1021/bi8014357] [PMID:  18989932] 
[58] 
Hebda JA, Saraogi I, Magzoub M, Hamilton AD, Miranker AD. A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes. Chem Biol  2009; 16(9): 943-50.
[http://dx.doi.org/10.1016/j.chembiol.2009.08.013] [PMID:  19778722] 
[59] 
Lopes DHJ, Meister A, Gohlke A, Hauser A, Blume A, Winter R. Mechanism of islet amyloid polypeptide fibrillation at lipid interfaces studied by infrared reflection absorption spectroscopy. Biophys J  2007; 93(9): 3132-41.
[http://dx.doi.org/10.1529/biophysj.107.110635] [PMID:  17660321] 
[60] 
Williamson JA, Loria JP, Miranker AD. Helix stabilization precedes aqueous and bilayer-catalyzed fiber formation in islet amyloid polypeptide. J Mol Biol  2009; 393(2): 383-96.
[http://dx.doi.org/10.1016/j.jmb.2009.07.077] [PMID:  19647750] 
[61] 
Knight JD, Hebda JA, Miranker AD. Conserved and cooperative assembly of membrane-bound alpha-helical states of islet amyloid polypeptide. Biochemistry  2006; 45(31): 9496-508.
[http://dx.doi.org/10.1021/bi060579z] [PMID:  16878984] 
[62] 
Jayasinghe SA, Langen R. Membrane interaction of islet amyloid polypeptide. Biochim Biophys Acta  2007; 1768(8): 2002-9.
[http://dx.doi.org/10.1016/j.bbamem.2007.01.022] [PMID:  17349968] 
[63] 
Sparks S, Liu G, Robbins KJ, Lazo ND. Curcumin modulates the self-assembly of the islet amyloid polypeptide by disassembling α-helix. Biochem Biophys Res Commun  2012; 422(4): 551-5.
[http://dx.doi.org/10.1016/j.bbrc.2012.05.013] [PMID:  22579683] 
[64] 
Bram Y, Frydman-Marom A, Yanai I, Gilead S, Shaltiel-Karyo R, Amdursky N, et al. Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies. Sci Rep. Nature Publishing Group  2015; 4(1): 4267.
[65] 
Koo BW, Hebda JA, Miranker AD. Amide inequivalence in the fibrillar assembly of islet amyloid polypeptide. Protein Eng Des Sel  2008; 21(3): 147-54.
[http://dx.doi.org/10.1093/protein/gzm076] [PMID:  18299291] 
[66] 
Buchanan LE, Dunkelberger EB, Tran HQ, et al. Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet. Proc Natl Acad Sci USA  2013; 110(48): 19285-90.
[http://dx.doi.org/10.1073/pnas.1314481110] [PMID:  24218609] 
[67] 
Liu N, Duan M, Yang M. Structural Properties of Human IAPP Dimer in Membrane Environment Studied by All-Atom Molecular Dynamics Simulations. Sci Rep  2017; 7(1): 7915.
[http://dx.doi.org/10.1038/s41598-017-08504-x] [PMID:  28801684] 
[68] 
Zhao J, Yu X, Liang G, Zheng J. Heterogeneous triangular structures of human islet amyloid polypeptide (amylin) with internal hydrophobic cavity and external wrapping morphology reveal the polymorphic nature of amyloid fibrils. Biomacromolecules  2011; 12(5): 1781-94.
[http://dx.doi.org/10.1021/bm2001507] [PMID:  21428404] 
[69] 
Wineman-Fisher V, Atsmon-Raz Y, Miller Y. Orientations of residues along the β-arch of self-assembled amylin fibril-like structures lead to polymorphism. Biomacromolecules  2015; 16(1): 156-65.
[http://dx.doi.org/10.1021/bm501326y] [PMID:  25420121] 
[70] 
Radovan D, Smirnovas V, Winter R. Effect of pressure on islet amyloid polypeptide aggregation: revealing the polymorphic nature of the fibrillation process. Biochemistry  2008; 47(24): 6352-60.
[http://dx.doi.org/10.1021/bi800503j] [PMID:  18498175] 
[71] 
Dias CL, Karttunen M, Chan HS. Hydrophobic interactions in the formation of secondary structures in small peptides. Phys Rev E Stat Nonlin Soft Matter Phys  2011; 84(4 Pt 1)041931
[http://dx.doi.org/10.1103/PhysRevE.84.041931] [PMID:  22181199] 
[72] 
Betsholtz C, Christmansson L, Engström U, et al. Sequence divergence in a specific region of islet amyloid polypeptide (IAPP) explains differences in islet amyloid formation between species. FEBS Lett  1989; 251(1-2): 261-4.
[http://dx.doi.org/10.1016/0014-5793(89)81467-X] [PMID:  2666169] 
[73] 
Jaikaran ET, Higham CE, Serpell LC, et al. Identification of a novel human islet amyloid polypeptide beta-sheet domain and factors influencing fibrillogenesis. J Mol Biol  2001; 308(3): 515-25.
[http://dx.doi.org/10.1006/jmbi.2001.4593] [PMID:  11327784] 
[74] 
Tenidis K, Waldner M, Bernhagen J, et al. Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties. J Mol Biol  2000; 295(4): 1055-71.
[http://dx.doi.org/10.1006/jmbi.1999.3422] [PMID:  10656810] 
[75] 
Gilead S, Gazit E. The role of the 14-20 domain of the islet amyloid polypeptide in amyloid formation. Exp Diabetes Res 2008.2008256954
[http://dx.doi.org/10.1155/2008/256954] [PMID:  18566678] 
[76] 
Pillay K, Govender P. Amylin uncovered: a review on the polypeptide responsible for type II diabetes. BioMed Res Int  2013; 2013826706
[http://dx.doi.org/10.1155/2013/826706] [PMID:  23607096] 
[77] 
Khemtémourian L, Engel MFM, Liskamp RMJ, Höppener JWM, Killian JA. The N-terminal fragment of human islet amyloid polypeptide is non-fibrillogenic in the presence of membranes and does not cause leakage of bilayers of physiologically relevant lipid composition. Biochim Biophys Acta  2010; 1798(9): 1805-11.
[http://dx.doi.org/10.1016/j.bbamem.2010.05.022] [PMID:  20570648] 
[78] 
Louros NN, Tsiolaki PL, Zompra AA, et al. Structural studies and cytotoxicity assays of “aggregation-prone” IAPP(8-16) and its non-amyloidogenic variants suggest its important role in fibrillogenesis and cytotoxicity of human amylin. Biopolymers  2015; 104(3): 196-205.
[http://dx.doi.org/10.1002/bip.22650] [PMID:  25913357] 
[79] 
Qi R, Luo Y, Ma B, Nussinov R, Wei G. Conformational distribution and α-helix to β-sheet transition of human amylin fragment dimer. Biomacromolecules  2014; 15(1): 122-31.
[http://dx.doi.org/10.1021/bm401406e] [PMID:  24313776] 
[80] 
Milardi D, Sciacca MFM, Pappalardo M, Grasso DM, La Rosa C. The role of aromatic side-chains in amyloid growth and membrane interaction of the islet amyloid polypeptide fragment LANFLVH. Eur Biophys J  2011; 40(1): 1-12.
[http://dx.doi.org/10.1007/s00249-010-0623-x] [PMID:  20809197] 
[81] 
Nilsson MR, Raleigh DP. Analysis of amylin cleavage products provides new insights into the amyloidogenic region of human amylin. J Mol Biol  1999; 294(5): 1375-85.
[http://dx.doi.org/10.1006/jmbi.1999.3286] [PMID:  10600392] 
[82] 
Bruno E, Pereira C, Roman KP, et al. IAPP aggregation and cellular toxicity are inhibited by 1,2,3,4,6-penta-O-galloyl-β-D-glucose. Amyloid  2013; 20(1): 34-8.
[http://dx.doi.org/10.3109/13506129.2012.762761] [PMID:  23339420] 
[83] 
Zhao L, Xin Y, Li Y, Yang X, Luo L, Meng F. Ultraeffective inhibition of amyloid fibril assembly by nanobody-gold nanoparticle conjugates. Bioconjug Chem  2019; 30(1): 29-33.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00797] [PMID:  30585717] 
[84] 
Shaykhalishahi H, Mirecka EA, Gauhar A, et al. A β-hairpin-binding protein for three different disease-related amyloidogenic proteins. ChemBioChem  2015; 16(3): 411-4.
[http://dx.doi.org/10.1002/cbic.201402552] [PMID:  25557164] 
[85] 
Azzam SK, Jang H, Choi MC, Alsafar H, Lukman S, Lee S. Inhibition of Human Amylin Aggregation and Cellular Toxicity by Lipoic Acid and Ascorbic Acid. Mol Pharm  2018; 15(6): 2098-106.
[http://dx.doi.org/10.1021/acs.molpharmaceut.7b01009] [PMID:  29709194] 
[86] 
López LC, Varea O, Navarro S, et al. Benzbromarone, quercetin, and folic acid inhibit amylin aggregation. Int J Mol Sci  2016; 17(6)E964
[http://dx.doi.org/10.3390/ijms17060964] [PMID:  27322259] 
[87] 
Lopes DHJ, Attar A, Nair G, et al. Molecular tweezers inhibit islet amyloid polypeptide assembly and toxicity by a new mechanism. ACS Chem Biol  2015; 10(6): 1555-69.
[http://dx.doi.org/10.1021/acschembio.5b00146] [PMID:  25844890] 
[88] 
Alghrably M, Czaban I, Jaremko Ł, Jaremko M. Interaction of
	amylin species with transition metals and membranes. J Inorg Biochem
	Elsevier 191(6): 69-76. 2019.
[89] 
Fortin JS, Benoit-Biancamano M-O. Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs. Can J Physiol Pharmacol  2016; 94(1): 35-48.
[http://dx.doi.org/10.1139/cjpp-2015-0117] [PMID:  26524404] 
[90] 
Cao P, Raleigh DP. Analysis of the inhibition and remodeling of islet amyloid polypeptide amyloid fibers by flavanols. Biochemistry  2012; 51(13): 2670-83.
[http://dx.doi.org/10.1021/bi2015162] [PMID:  22409724] 
[91] 
Meng F, Abedini A, Plesner A, Verchere CB, Raleigh DP. The flavanol (-)-epigallocatechin 3-gallate inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured cells against IAPP-induced toxicity. Biochemistry  2010; 49(37): 8127-33.
[http://dx.doi.org/10.1021/bi100939a] [PMID:  20707388] 
[92] 
Young LM, Cao P, Raleigh DP, Ashcroft AE, Radford SE. Ion mobility spectrometry-mass spectrometry defines the oligomeric intermediates in amylin amyloid formation and the mode of action of inhibitors. J Am Chem Soc  2014; 136(2): 660-70.
[http://dx.doi.org/10.1021/ja406831n] [PMID:  24372466] 
[93] 
Franko A, Rodriguez Camargo DC, Böddrich A, et al. Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice. Sci Rep  2018; 8(1): 1116.
[http://dx.doi.org/10.1038/s41598-017-18807-8] [PMID:  29348618] 
[94] 
Mo Y, Lei J, Sun Y, Zhang Q, Wei G. Conformational Ensemble of hIAPP Dimer: Insight into the Molecular Mechanism by which a Green Tea Extract inhibits hIAPP Aggregation. Sci Rep  2016; 6: 33076.
[http://dx.doi.org/10.1038/srep33076] [PMID:  27620620] 
[95] 
Engel MFM. vandenAkker CC, Schleeger M, Velikov KP, Koenderink GH, Bonn M. The polyphenol EGCG inhibits amyloid formation less efficiently at phospholipid interfaces than in bulk solution. J Am Chem Soc  2012; 134(36): 14781-8.
[http://dx.doi.org/10.1021/ja3031664] [PMID:  22889183] 
[96] 
Bahramikia S, Yazdanparast R. Inhibition of human islet amyloid polypeptide or amylin aggregation by two manganese-salen derivatives. Eur J Pharmacol  2013; 707(1-3): 17-25.
[http://dx.doi.org/10.1016/j.ejphar.2013.03.017] [PMID:  23528352] 
[97] 
Shi Y, Lv W, Jiao A, Zhang C, Zhang J. A novel pentapeptide inhibitor reduces amyloid deposit formation by direct interaction with hiapp.  Int J Endocrinol Hindawi 2019; pp. 1-9.
[http://dx.doi.org/10.1155/2019/9062032] 
[98] 
Yan L-M, Tatarek-Nossol M, Velkova A, Kazantzis A, Kapurniotu A. Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis. Proc Natl Acad Sci USA  2006; 103(7): 2046-51.
[http://dx.doi.org/10.1073/pnas.0507471103] [PMID:  16467158] 
[99] 
Gurzov EN, Wang B, Pilkington EH, et al. Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-Cell Toxicity by OH-Terminated PAMAM Dendrimer. Small  2016; 12(12): 1615-26.
[http://dx.doi.org/10.1002/smll.201502317] [PMID:  26808649] 
[100] 
Knight JD, Williamson JA, Miranker AD. Interaction of membrane-bound islet amyloid polypeptide with soluble and crystalline insulin. Protein Sci  2008; 17(10): 1850-6.
[http://dx.doi.org/10.1110/ps.036350.108] [PMID:  18765820] 
[101] 
Knight JD, Miranker AD. Phospholipid catalysis of diabetic amyloid assembly. J Mol Biol  2004; 341(5): 1175-87.
[http://dx.doi.org/10.1016/j.jmb.2004.06.086] [PMID:  15321714] 
[102] 
Noor H, Cao P, Raleigh DP. Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers. Protein Sci  2012; 21(3): 373-82.
[http://dx.doi.org/10.1002/pro.2023] [PMID:  22238175] 
[103] 
Zelus C, Fox A, Calciano A, Faridian BS, Nogaj LA, Moffet DA. Myricetin inhibits islet amyloid polypeptide (iapp) aggregation and rescues living mammalian cells from iapp toxicity. Open Biochem J  2012; 6: 66-70.
[http://dx.doi.org/10.2174/1874091X01206010066] [PMID:  22792130] 
[104] 
Paul A, Kalita S, Kalita S, Sukumar P, Mandal B. Disaggregation of amylin aggregate by novel conformationally restricted aminobenzoic acid containing α/β and α/γ hybrid peptidomimetics. Sci Rep  2017; 7: 40095.
[http://dx.doi.org/10.1038/srep40095] [PMID:  28054630] 
[105] 
Mishra R, Sellin D, Radovan D, Gohlke A, Winter R. Inhibiting islet amyloid polypeptide fibril formation by the red wine compound resveratrol. ChemBioChem  2009; 10(3): 445-9.
[http://dx.doi.org/10.1002/cbic.200800762] [PMID:  19165839] 
[106] 
Li X, Wan M, Gao L, Fang W. Mechanism of inhibition of human islet amyloid polypeptide-induced membrane damage by a small organic fluorogen. Sci Rep  2016; 6: 21614.
[http://dx.doi.org/10.1038/srep21614] [PMID:  26887358] 
[107] 
Ren B, Liu Y, Zhang Y, et al. Tanshinones inhibit hIAPP aggregation, disaggregate preformed hIAPP fibrils, and protect cultured cells. J Mater Chem B. Royal Society of Chemistry  2018; 6(1): 56-67.
[108] 
Bram Y, Lampel A, Shaltiel-Karyo R, et al. Monitoring and targeting the initial dimerization stage of amyloid self-assembly. Angew Chem Int Ed Engl  2015; 54(7): 2062-7.
[http://dx.doi.org/10.1002/anie.201408744] [PMID:  25533189] 
[109] 
Wang S-T, Lin Y, Hsu C-C, Amdursky N, Spicer CD, Stevens MM. Probing amylin fibrillation at an early stage via a tetracysteine-recognising fluorophore. Talanta  2017; 173: 44-50.
[http://dx.doi.org/10.1016/j.talanta.2017.05.015] [PMID:  28602190] 
[110] 
Lukman S, Sim K, Li J, Chen Y-PP. Interacting amino acid preferences of 3d pattern pairs at the binding sites of transient and obligate protein complexes. Proceedings of the 6th Asia-Pacific Bioinformatics Conference.  69-78.
[111] 
De Carufel CA, Quittot N, Nguyen PT, Bourgault S. Delineating the role of helical intermediates in natively unfolded polypeptide amyloid assembly and cytotoxicity. Angew Chem Int Ed Engl  2015; 54(48): 14383-7.
[http://dx.doi.org/10.1002/anie.201507092] [PMID:  26440575] 
[112] 
Zhao D-S, Chen Y-X, Li Y-M. Rational design of an orthosteric regulator of hIAPP aggregation. Chem Commun (Camb)  2015; 51(11): 2095-8.
[http://dx.doi.org/10.1039/C4CC06739H] [PMID:  25536011] 
[113] 
Daval M, Bedrood S, Gurlo T, et al. The effect of curcumin on human islet amyloid polypeptide misfolding and toxicity. Amyloid  2010; 17(3-4): 118-28.
[http://dx.doi.org/10.3109/13506129.2010.530008] [PMID:  21067307] 
[114] 
Pithadia A, Brender JR, Fierke CA, Ramamoorthy A. inhibition of iapp aggregation and toxicity by natural products and derivatives. J Diabetes Res  2016; 20162046327
[http://dx.doi.org/10.1155/2016/2046327] [PMID:  26649317] 
[115] 
Scrocchi LA, Chen Y, Waschuk S, et al. Design of peptide-based inhibitors of human islet amyloid polypeptide fibrillogenesis. J Mol Biol  2002; 318(3): 697-706.
[http://dx.doi.org/10.1016/S0022-2836(02)00164-X] [PMID:  12054816] 
[116] 
Tatarek-Nossol M, Yan L-M, Schmauder A, Tenidis K, Westermark G, Kapurniotu A. Inhibition of hIAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid- core-containing hexapeptide. Chem Biol  2005; 12(7): 797-809.
[http://dx.doi.org/10.1016/j.chembiol.2005.05.010] [PMID:  16039527] 
[117] 
Monsellier E, Chiti F. Prevention of amyloid-like aggregation as a driving force of protein evolution. EMBO Rep  2007; 8(8): 737-42.
[http://dx.doi.org/10.1038/sj.embor.7401034] [PMID:  17668004] 
[118] 
Rijkers DTS, Höppener JWM, Posthuma G, Lips CJM, Liskamp RMJ. Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and alpha-hydroxy acid residue containing peptides. Chemistry  2002; 8(18): 4285-91.
[http://dx.doi.org/10.1002/1521-3765(20020916)8:18<4285:AID-CHEM4285>3.0.CO;2-0] [PMID:  12298020] 
[119] 
Susa AC, Wu C, Bernstein SL, et al. Defining the molecular basis of amyloid inhibitors: human islet amyloid polypeptide-insulin interactions. J Am Chem Soc  2014; 136(37): 12912-9.
[http://dx.doi.org/10.1021/ja504031d] [PMID:  25144879] 
[120] 
Cui W, Ma J-W, Lei P, et al. Insulin is a kinetic but not a thermodynamic inhibitor of amylin aggregation. FEBS J  2009; 276(12): 3365-71.
[http://dx.doi.org/10.1111/j.1742-4658.2009.07061.x] [PMID:  19438709] 
[121] 
Zhou S, Wang Q, Ren M, Zhang A, Liu H, Yao X. Molecular dynamics simulation on the inhibition mechanism of peptide-based inhibitor of islet amyloid polypeptide (IAPP) to islet amyloid polypeptide (IAPP22-28) oligomers. Chem Biol Drug Des  2017; 90(1): 31-9.
[http://dx.doi.org/10.1111/cbdd.12924] [PMID:  28004495] 
[122] 
Despa F, Decarli C. Amylin: what might be its role in Alzheimer’s disease and how could this affect therapy? Expert Rev Proteomics  2013; 10(5): 403-5.
[http://dx.doi.org/10.1586/14789450.2013.841549] [PMID:  24117198] 
[123] 
Grizzanti J, Corrigan R, Servizi S, Casadesus G. Amylin signaling in diabetes and alzheimer’s disease: therapy or pathology? In: SciAccess Publishers.   2019; Vol. 4: pp. 12-6.
[124] 
Hölscher C. Drugs developed for treatment of diabetes show protective effects in Alzheimer’s and Parkinson’s diseases. Sheng Li Xue Bao  2014; 66(5): 497-510.
[PMID:  25331995] 
[125] 
McClean PL, Hölscher C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology  2014; 86: 241-58.
[http://dx.doi.org/10.1016/j.neuropharm.2014.07.015] [PMID:  25107586] 
[126] 
Jackson K, Barisone GA, Diaz E, Jin L-W, DeCarli C, Despa F. Amylin deposition in the brain: A second amyloid in Alzheimer disease? Ann Neurol  2013; 74(4): 517-26.
[http://dx.doi.org/10.1002/ana.23956] [PMID:  23794448] 
[127] 
Despa S, Margulies KB, Chen L, et al. Hyperamylinemia contributes to cardiac dysfunction in obesity and diabetes: a study in humans and rats. Circ Res  2012; 110(4): 598-608.
[http://dx.doi.org/10.1161/CIRCRESAHA.111.258285] [PMID:  22275486] 
[128] 
Gong W, Liu ZH, Zeng CH, et al. Amylin deposition in the kidney of patients with diabetic nephropathy. Kidney Int  2007; 72(2): 213-8.
[http://dx.doi.org/10.1038/sj.ki.5002305] [PMID:  17495860] 
[129] 
Zhang N, Yang S, Wang C, Zhang J, Huo L, Cheng Y, et al. Multiple target of hAmylin on rat primary hippocampal neurons.  Neuropharmacology  113(Pt A): 241-51.2017.
[http://dx.doi.org/10.1016/j.neuropharm.2016.07.008] 
[130] 
Schultz N, Byman E, Fex M, Wennström M. Amylin alters human brain pericyte viability and NG2 expression. J Cereb Blood Flow Metab  2017; 37(4): 1470-82.
[http://dx.doi.org/10.1177/0271678X16657093] [PMID:  27354094] 
[131] 
Li Z, Kelly L, Heiman M, Greengard P, Friedman JM. Hypothalamic amylin acts in concert with leptin to regulate food intake. Cell Metab  2015; 22(6): 1059-67.
[http://dx.doi.org/10.1016/j.cmet.2015.10.012] [PMID:  26655697] 
[132] 
Ferrier GJ, Pierson AM, Jones PM, Bloom SR, Girgis SI, Legon S. Expression of the rat amylin (IAPP/DAP) gene. J Mol Endocrinol  1989; 3(1): R1-4.
[http://dx.doi.org/10.1677/jme.0.003R001] [PMID:  2525914] 
[133] 
Mohamed LA, Zhu H, Mousa YM, Wang E, Qiu WQ, Kaddoumi A. Amylin Enhances Amyloid-β Peptide Brain to Blood Efflux Across the Blood-Brain Barrier. J Alzheimers Dis  2017; 56(3): 1087-99.
[http://dx.doi.org/10.3233/JAD-160800] [PMID:  28059785] 
[134] 
Roth JD. Amylin and the regulation of appetite and adiposity: recent advances in receptor signaling, neurobiology and pharmacology. Curr Opin Endocrinol Diabetes Obes  2013; 20(1): 8-13.
[http://dx.doi.org/10.1097/MED.0b013e32835b896f] [PMID:  23183359] 
[135] 
Edvinsson L, Goadsby PJ, Uddman R. Amylin: localization, effects on cerebral arteries and on local cerebral blood flow in the cat. ScientificWorldJournal  2001; 1: 168-80.
[http://dx.doi.org/10.1100/tsw.2001.23] [PMID:  12805660] 
[136] 
Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes  2004; 53(2): 474-81.
[http://dx.doi.org/10.2337/diabetes.53.2.474] [PMID:  14747300] 
[137] 
Adler BL, Yarchoan M, Hwang HM, et al. Neuroprotective effects of the amylin analogue pramlintide on Alzheimer’s disease pathogenesis and cognition. Neurobiol Aging  2014; 35(4): 793-801.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.10.076] [PMID:  24239383] 
[138] 
Qiu WQ, Zhu H. Amylin and its analogs: a friend or foe for the treatment of Alzheimer’s disease? Front Aging Neurosci  2014; 6: 186.
[http://dx.doi.org/10.3389/fnagi.2014.00186] [PMID:  25120481] 
[139] 
Zhu H, Stern RA, Tao Q, et al. An amylin analog used as a challenge test for Alzheimer’s disease. Alzheimers Dement (N Y)  2017; 3(1): 33-43.
[http://dx.doi.org/10.1016/j.trci.2016.12.002] [PMID:  28503657] 
[140] 
Zhu H, Wang X, Wallack M, et al. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer’s disease. Mol Psychiatry  2015; 20(2): 252-62.
[http://dx.doi.org/10.1038/mp.2014.17] [PMID:  24614496] 
[141] 
Cao P, Meng F, Abedini A, Raleigh DP. The ability of rodent islet amyloid polypeptide to inhibit amyloid formation by human islet amyloid polypeptide has important implications for the mechanism of amyloid formation and the design of inhibitors. Biochemistry  2010; 49(5): 872-81.
[http://dx.doi.org/10.1021/bi901751b] [PMID:  20028124] 
[142] 
Middleton CT, Marek P, Cao P, et al. Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. Nat Chem  2012; 4(5): 355-60.
[http://dx.doi.org/10.1038/nchem.1293] [PMID:  22522254] 
[143] 
Cho W-J, Trikha S, Jeremic AM. Cholesterol regulates assembly of human islet amyloid polypeptide on model membranes. J Mol Biol  2009; 393(3): 765-75.
[http://dx.doi.org/10.1016/j.jmb.2009.08.055] [PMID:  19720065] 
[144] 
Zhang X, St Clair JR, London E, Raleigh DP. Islet amyloid polypeptide membrane interactions: effects of membrane composition. Biochemistry  2017; 56(2): 376-90.
[http://dx.doi.org/10.1021/acs.biochem.6b01016] [PMID:  28054763] 
[145] 
Tomasello MF, Sinopoli A, Attanasio F, et al. Molecular and cytotoxic properties of hIAPP17-29 and rIAPP17-29 fragments: a comparative study with the respective full-length parent polypeptides. Eur J Med Chem  2014; 81: 442-55.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.038] [PMID:  24859763] 
[146] 
Trikha S, Jeremic AM. Distinct internalization pathways of human amylin monomers and its cytotoxic oligomers in pancreatic cells. PLoS One  2013; 8(9)e73080
[http://dx.doi.org/10.1371/journal.pone.0073080] [PMID:  24019897] 
[147] 
He B, Lu C, Zheng G, et al. Combination therapeutics in complex diseases. J Cell Mol Med  2016; 20(12): 2231-40.
[http://dx.doi.org/10.1111/jcmm.12930] [PMID:  27605177] 
[148] 
Sulatskaya AI, Maskevich AA, Kuznetsova IM, Uversky VN, Turoverov KK. Fluorescence quantum yield of thioflavin T in rigid isotropic solution and incorporated into the amyloid fibrils. PLoS One  2010; 5(10)e15385
[http://dx.doi.org/10.1371/journal.pone.0015385] [PMID:  21048945] 
[149] 
Guo J, Zhang Y, Ning L, Jiao P, Liu H, Yao X. Stabilities and structures of islet amyloid polypeptide (IAPP22-28) oligomers: from dimer to 16-mer. Biochim Biophys Acta  2014; 1840(1): 357-66.
[http://dx.doi.org/10.1016/j.bbagen.2013.09.012] [PMID:  24041993] 
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DOI https://dx.doi.org/10.2174/1389450120666190719164316	Print ISSN 1389-4501
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Current Drug Targets

Computational and Experimental Approaches to Design Inhibitors of Amylin Aggregation

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New drug therapy for eye diseases

Current Drug Targets

Computational and Experimental Approaches to Design Inhibitors of Amylin Aggregation

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