Molecular Tweezers Targeting Transthyretin Amyloidosis

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• 作者：Nelson Ferreira (1)
  Alda Pereira-Henriques (1)
  Aida Attar (2) (3)
  Frank-Gerrit Kl?rner (4)
  Thomas Schrader (4)
  Gal Bitan (2) (3) (5)
  Luís Gales (1) (6)
  Maria Jo?o Saraiva (1) (6)
  Maria Rosário Almeida (1) (6)
  
• 关键词：Molecular tweezers ; Transthyretin ; Amyloid ; Familial amyloidotic polyneuropathy
• 刊名：Neurotherapeutics
• 出版年：2014
• 出版时间：April 2014
• 年：2014
• 卷：11
• 期：2
• 页码：450-461
• 全文大小：
• 参考文献：1. Blake CC, Geisow MJ, Oatley SJ, Rérat B, Rérat C. Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 A. J Mol Biol 1978;21:339-356. CrossRef
  2. Andrade C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 1952;75:408-427. CrossRef
  3. Saraiva MJ, Costa PP, Goodman DS. Biochemical marker in familial amyloidotic polyneuropathy, Portuguese type. Family studies on the Transthyretin (prealbumin)-methionine-30 variant. J Clin Invest. 1985;76:2171-7. CrossRef
  4. Said G, Grippon S, Kirkpatrick P. Tafamidis. Nat Rev Drug Discov 2012;11:185-186. CrossRef
  5. Brett M, Persey MR, Reilly MM, et al. Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. Brain 1999;122:183-190. CrossRef
  6. Vidal R, Garzuly F, Budka H, et al. Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTR D18G). Am J Pathol 1996;148:361-366.
  7. Sekijima Y, Hammarstr?m P, Matsumura M, et al. Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology. Lab Invest 2003;83:409-417. CrossRef
  8. Ellie E, Camou F, Vital A, et al. Recurrent subarachnoid hemorrhage associated with a new transthyretin variant (Gly53Glu). Neurology 2001;57:135-137. CrossRef
  9. Cornwell GG 3rd, Sletten K, Johansson B, Westermark P. Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealbumin. Biochem Biophys Res Commun 1988;154:648-653. CrossRef
  10. Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol 2005;62:1057-1062. CrossRef
  11. Almeida MR, Saraiva MJ. Clearance of extracellular misfolded proteins in systemic amyloidosis: experience with transthyretin. FEBS Lett 2012;586:2891-2896. CrossRef
  12. Sinha S, Lopes DH, Du Z, Pang ES, Shanmugam A, Lomakin A, et al. Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins. J Am Chem Soc 2011;133:16958-16969. CrossRef
  13. Talbiersky P, Bastkowski F, Kl?rner FG, Schrader T. Molecular clip and tweezer introduce new mechanisms of enzyme inhibition. J Am Chem Soc 2008;130:9824-9828. CrossRef
  14. Dutt S, Wilch C, Gersthagen T, et al. Molecular tweezers with varying anions: a comparative study. J Org Chem 2013;78:6721-6734. CrossRef
  15. Furuya H, Saraiva MJ, Gawinowicz MA, et al. Production of recombinant human transthyretin with biological activities toward the understanding of the molecular basis of familial amyloidotic polyneuropathy (FAP). Biochemistry 1991;30:2415-2421. CrossRef
  16. Cardoso I, Almeida MR, Ferreira N, Arsequell G, Valencia G, Saraiva MJ. Comparative in vitro and ex vivo activities of selected inhibitors of transthyretin aggregation: relevance in drug design. Biochem J 2007;408:131-138. CrossRef
  17. Santos SD, Fernandes R, Saraiva MJ. The heat shock response modulates transthyretin deposition in the peripheral and autonomic nervous systems. Neurobiol Aging 2010;31:280-289. CrossRef
  18. Ferreira N, Santos SA, Domingues MR, Saraiva MJ, Almeida MR. Dietary curcumin counteracts extracellular transthyretin deposition: insights on the mechanism of amyloid inhibition. Biochim Biophys Acta 2013;1832:39-45.
  19. Almeida MR, Macedo B, Cardoso I, et al. Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative. Biochem J 2004;381:351-356. CrossRef
  20. Ferreira N, Cardoso I, Domingues MR, et al. Binding of epigallocatechin-3-gallate to transthyretin modulates its amyloidogenicity. FEBS Lett 2009;583:3569-3576. CrossRef
  21. Ferreira N, Saraiva MJ, Almeida MR. Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation. FEBS Lett 2011;585:2424-2430. CrossRef
  22. Ferreira N, Saraiva MJ, Almeida MR. Epigallocatechin-3-gallate as a potential therapeutic drug for TTR-related amyloidosis: “in vivo-evidence from FAP mice models. PLoS One 2012;7:e29933. CrossRef
  23. Attar A, Ripoli C, Riccardi E, et al. Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers. Brain 2012;135:3735-3748. CrossRef
  24. Kayed R, Head E, Thompson JL, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003;300:486-489. CrossRef
  25. Sousa MM, Cardoso I, Fernandes R, Guimar?es A, Saraiva MJ. Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. Am J Pathol 2001;159:1993-2000. CrossRef
  26. Teixeira PF, Cerca F, Santos SD, Saraiva MJ. Endoplasmic reticulum stress associated with extracellular aggregates. Evidence from transthyretin deposition in familial amyloid polyneuropathy. J Biol Chem 2006;281:21998-22003. CrossRef
  27. Macedo B, Batista AR, Ferreira N, Almeida MR, Saraiva MJ. Anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model of Familial Amyloidotic Polyneuropathy. Biochim Biophys Acta 2008;1782:517-522. CrossRef
  28. Palhano FL, Lee J, Grimster NP, Kelly JW. Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils. J Am Chem Soc 2013;135:7503-7510. CrossRef
  29. Bier D, Rose R, Bravo-Rodriguez K, et al. Molecular tweezers modulate 14-3-3 protein-protein interactions. Nat Chem 2013;5:234-239. CrossRef
  30. Sinha S, Du Z, Maiti P, et al. Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. ACS Chem Neurosci 2012;3:451-458. CrossRef
  31. Mandel SA, Amit T, Weinreb O, Reznichenko L, Youdim MB. Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS Neurosci Ther 2008;14:352-365. CrossRef
  32. Weinreb O, Amit T, Mandel S, Youdim MB. Neuroprotective molecular mechanisms of (-)-epigallocatechin-3-gallate: a reflective outcome of its antioxidant, iron chelating and neuritogenic properties. Genes Nutr 2009;4:283-296. CrossRef
  33. Ehrnhoefer DE, Bieschke J, Boeddrich A, et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 2008;15:558-566. CrossRef
  34. Wang SH, Liu FF, Dong XY, Sun Y. Thermodynamic analysis of the molecular interactions between amyloid beta-peptide 42 and (-)-epigallocatechin-3-gallate. J Phys Chem B 2010;114:11576-11583. CrossRef
  35. Prabhudesai S, Sinha S, Attar A, et al. A novel “molecular tweezer-inhibitor of α-synuclein neurotoxicity in vitro and in vivo. Neurotherapeutics 2012;9:464-476. CrossRef
  36. Sousa MM, do Amaral JB, Guimar?es A, Saraiva MJ. Up-regulation of the extracellular matrix remodeling genes, biglycan, neutrophil gelatinase-associated lipocalin, and matrix metalloproteinase-9 in familial amyloid polyneuropathy. FASEB J 2005; 19:124-126.
  37. Pan XD, Zhu YG, Lin N, et al. Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease. Mol Neurodegener 2011;6:45. CrossRef
  38. Lambert JD, Lee MJ, Lu H, et al. Epigallocatechin-3-gallate is absorbed but extensively glucuronidated following oral administration to mice. J Nutr 2003;133:4172-4177.
  39. Chauhan A, Ray I, Chauhan VP. Interaction of amyloid beta-protein with anionic phospholipids: possible involvement of Lys28 and C-terminus aliphatic amino acids. Neurochem Res 2000;25:423-429. CrossRef
  40. Bokvist M, Lindstr?m F, Watts A, Gr?bner G. Two types of Alzheimer's beta-amyloid (1-40) peptide membrane interactions: aggregation preventing transmembrane anchoring versus accelerated surface fibril formation. J Mol Biol 2004;335:1039-1049. CrossRef
  41. Sinha S, Lopes DH, Bitan G. A key role for lysine residues in amyloid β-protein folding, assembly, and toxicity. ACS Chem Neurosci 2012;3:473-481. CrossRef
  42. Attar A, Bitan G. Disrupting self-assembly and toxicity of amyloidogenic protein oligomers by “molecular tweezers--from the test tube to animal models. Curr Pharm Des 2013 Jul 11 [Epub ahead of print].
  
• 作者单位：Nelson Ferreira (1)
  Alda Pereira-Henriques (1)
  Aida Attar (2) (3)
  Frank-Gerrit Kl?rner (4)
  Thomas Schrader (4)
  Gal Bitan (2) (3) (5)
  Luís Gales (1) (6)
  Maria Jo?o Saraiva (1) (6)
  Maria Rosário Almeida (1) (6)
  
  1. IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal
  2. Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
  3. Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, USA
  4. Faculty of Chemistry, University of Duisburg-Essen, Essen, Germany
  5. Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA, USA
  6. ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
  
• ISSN：1878-7479

文摘

Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the “molecular tweezers- CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer’s disease and Parkinson’s disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.