BRAIN and NERVE－神経研究の進歩75巻10号

2023年10月発行

総説

設計可能な抗アミロイド化合物を用いた，がん，2型糖尿病，神経変性疾患に対する疾患横断的な戦略

著者： 高松芳樹¹ 橋本款¹

所属機関： ¹公益財団法人東京都医学総合研究所

ページ範囲：P.1143 - P.1148

文献概要

アミロイド蛋白は神経変性疾患だけでなく，がんや2型糖尿病など，さまざまな疾患に関与する。クライオ電子顕微鏡単粒子解析法（クライオEM）の進歩により，アミロイド蛋白に共通する構造に対してその線維化を阻止する化合物を設計する，いくつかの戦略コンセプトを見出すことができる。これらは異なる種類のアミロイド蛋白に適用可能であり，疾患の垣根を超えた応用が期待される。このように広く適用可能な戦略コンセプトとして，ペプチド模倣型フォルダマー，立体ジッパー阻害ペプチド，ディフェニルピラゾール誘導体およびアミロイド線維を分解する化合物を用いた手法について紹介する。

参考文献

1）Buxbaum JN, Dispenzieri A, Eisenberg DS, Fändrich M, Merlini G, et al: Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee. Amyloid 29: 213-219, 2022

2）Benson MD, Buxbaum JN, Eisenberg DS, Merlini G, Saraiva MJM, et al: Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid 25: 215-219, 2018

3）Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, et al: Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid 17: 101-104, 2010

4）Peña-Díaz S, García-Pardo J, Ventura S: Development of small molecules targeting α-synuclein aggregation: a promising strategy to treat Parkinson's disease. Pharmaceutics 15: 839, 2023［doi: 10.3390/pharmaceutics15030839］

5）Appella DH, Christianson LA, Klein DA, Powell DR, Huang X, et al: Residue-based control of helix shape in beta-peptide oligomers. Nature 387: 381-384, 1997

6）Goodman CM, Choi S, Shandler S, DeGrado WF: Foldamers as versatile frameworks for the design and evolution of function. Nat Chem Biol 3: 252-262, 2007

7）George KL, Horne WS: Foldamer tertiary structure through sequence-guided protein backbone alteration. Acc Chem Res 51: 1220-1228, 2018

8）Rinaldi S: The diverse world of foldamers: endless possibilities of self-assembly. Molecules 25: 3276, 2020［doi: 10.3390/molecules25143276］

9）Kumar S, Birol M, Schlamadinger DE, Wojcik SP, Rhoades E, et al: Foldamer-mediated manipulation of a pre-amyloid toxin. Nat Commun 7: 11412, 2016［doi: 10.1038/ncomms11412］

10）Kahn SE, Andrikopoulos S, Verchere CB: Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 48: 241-253, 1999

11）Hull RL, Westermark GT, Westermark P, Kahn SE: Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab 89: 3629-3643, 2004

12）Albariqi MM, Versteeg S, Brakkee EM, Coert JH, Elenbaas BO, et al: Human IAPP is a contributor to painful diabetic peripheral neuropathy. J Clin Invest 133: e156993, 2023［doi: 10.1172/JCI156993］

13）Davis JM, Tsou LK, Hamilton AD: Synthetic non-peptide mimetics of alpha-helices. Chem Soc Rev 36: 326-334, 2007

14）Rodriguez JM, Hamilton AD: Benzoylurea oligomers: synthetic foldamers that mimic extended alpha helices. Angew Chem Int Ed Engl 46: 8614-8617, 2007

15）Saraogi I, Hamilton AD: Alpha-Helix mimetics as inhibitors of protein-protein interactions. Biochem Soc Trans 36: 1414-1417, 2008

16）Williamson JA, Miranker AD: Direct detection of transient alpha-helical states in islet amyloid polypeptide. Protein Sci 16: 110-117, 2007

17）Hebda JA, Saraogi I, Magzoub M, Hamilton AD, Miranker AD: A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes. Chem Biol 16: 943-950, 2009

18）Ahmed J, Fitch TC, Donnelly CM, Joseph JA, Ball TD, et al: Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly. Nat Commun 13: 2273, 2022［doi: 10.1038/s41467-022-29724-4］

19）Kumar S, Henning-Knechtel A, Chehade I, Magzoub M, Hamilton AD: Foldamer-mediated structural rearrangement attenuates Aβ oligomerization and cytotoxicity. J Am Chem Soc 139: 17098-17108, 2017

20）Palanikumar L, Karpauskaite L, Al-Sayegh M, Chehade I, Alam M, et al: Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function. Nat Commun 12: 3962, 2021［doi: 10.1038/s41467-021-23985-1］

21）Tjernberg LO, Näslund J, Lindqvist F, Johansson J, Karlström AR, et al: Arrest of beta-amyloid fibril formation by a pentapeptide ligand. J Biol Chem 271: 8545-8548, 1996

22）Nelson R, Sawaya MR, Balbirnie M, Madsen AØ, Riekel C, et al: Structure of the cross-beta spine of amyloid-like fibrils. Nature 435: 773-778, 2005

23）Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, et al: Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447: 453-457, 2007

24）Sievers SA, Karanicolas J, Chang HW, Zhao A, Jiang L, et al: Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature 475: 96-100, 2011

25）Shi D, Nannenga BL, Iadanza MG, Gonen T: Three-dimensional electron crystallography of protein microcrystals. Elife 2: e01345, 2013［doi: 10.7554/eLife.01345］

26）Rodriguez JA, Ivanova MI, Sawaya MR, Cascio D, Reyes FE, et al: Structure of the toxic core of α-synuclein from invisible crystals. Nature 525: 486-490, 2015

27）Li B, Ge P, Murray KA, Sheth P, Zhang M, et al: Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nat Commun 9: 3609, 2018［doi: 10.1038/s41467-018-05971-2］

28）Sangwan S, Sahay S, Murray KA, Morgan S, Guenther EL, et al: Inhibition of synucleinopathic seeding by rationally designed inhibitors. Elife 9: e46775, 2020［doi: 10.7554/eLife.46775］

29）Seidler PM, Boyer DR, Rodriguez JA, Sawaya MR, Cascio D, et al: Structure-based inhibitors of tau aggregation. Nat Chem 10: 170-176, 2018

30）Cao Q, Boyer DR, Sawaya MR, Ge P, Eisenberg DS: Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils. Nat Struct Mol Biol 27: 653-659, 2020

31）Soragni A, Janzen DM, Johnson LM, Lindgren AG, Thai-Quynh Nguyen A, et al: A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas. Cancer Cell 29: 90-103, 2016

32）Bertsch U, Winklhofer KF, Hirschberger T, Bieschke J, Weber P, et al: Systematic identification of antiprion drugs by high-throughput screening based on scanning for intensely fluorescent targets. J Virol 79: 7785-7791, 2005

33）Schiffer NW, Broadley SA, Hirschberger T, Tavan P, Kretzschmar HA, et al: Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model. J Biol Chem 282: 9195-9203, 2007

34）Kostka M, Högen T, Danzer KM, Levin J, Habeck M, et al: Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283: 10992-11003, 2008

35）Hillmer AS, Putcha P, Levin J, Högen T, Hyman BT, et al: Converse modulation of toxic alpha-synuclein oligomers in living cells by N'-benzylidene-benzohydrazide derivates and ferric iron. Biochem Biophys Res Commun 391: 461-466, 2010

36）Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, et al: Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol 125: 795-813, 2013

37）Saravanan MS, Ryazanov S, Leonov A, Nicolai J, Praest P, et al: The small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers. Sci Rep 9: 19023, 2019［doi: 10.1038/s41598-019-54919-z］

38）Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, et al: EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A 107: 7710-7715, 2010

39）Bae SY, Kim S, Hwang H, Kim HK, Yoon HC, et al: Amyloid formation and disaggregation of α-synuclein and its tandem repeat (α-TR). Biochem Biophys Res Commun 400: 531-536, 2010

40）Caruana M, Högen T, Levin J, Hillmer A, Giese A, et al: Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds. FEBS Lett 585: 1113-1120, 2011

41）Saffari B, Amininasab M: Crocin inhibits the fibrillation of human α-synuclein and disassembles mature fibrils: experimental findings and mechanistic insights from molecular dynamics simulation. ACS Chem Neurosci 12: 4037-4057, 2021

42）Pujols J, Peña-Díaz S, Lázaro DF, Peccati F, Pinheiro F, et al: Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons. Proc Natl Acad Sci U S A 115: 10481-10486, 2018

43）Peña-Díaz S, Pujols J, Pinheiro F, Santos J, Pallarés I, et al: Inhibition of α-synuclein aggregation and mature fibril disassembling with a minimalistic compound, ZPDm. Front Bioeng Biotechnol 8: 588947, 2020［doi: 10.3389/fbioe.2020.588947］

44）Andrich K, Bieschke J: The effect of (-)-Epigallo-catechin-(3)-gallate on amyloidogenic proteins suggests a common mechanism. Adv Exp Med Biol 863: 139-161, 2015

45）Seidler PM, Murray KA, Boyer DR, Ge P, Sawaya MR, et al: Structure-based discovery of small molecules that disaggregate Alzheimer's disease tissue derived tau fibrils in vitro. Nat Commun 13: 5451, 2022

46）Murray KA, Hu CJ, Pan H, Lu J, Abskharon R, et al: Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils. Proc Natl Acad Sci U S A 120: e2217835120, 2023［doi: 10.1073/pnas.2217835120］