Familial cardiac amyloidosis: Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity

Science Translational Medicine

Volumn 3, Issue 97, 2011, Pages

  Alhamadsheh, Mamoun M ^a,b   Connelly, Stephen ^c   Cho, Ahryon ^a   Reixach, Natàlia ^c   Powers, Evan T ^c   Pan, Dorothy W ^a   Wilson, Ian A ^c   Kelly, Jeffery W ^c   Graef, Isabella A ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF THE PACIFIC   (United States)

^c SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2' FLUORO 3,4 DIHYDROXY 5 NITROBENZOPHENONE; CATECHOL DERIVATIVE; DICLOFENAC DERIVATIVE; DIFLUNISAL; NIFLUMIC ACID; PREALBUMIN; PROTEIN INHIBITOR; SCAFFOLD PROTEIN; STABILIZING AGENT; TETRAMER;

ARTICLE; BINDING AFFINITY; CARDIOMYOPATHY; CARDIOTOXICITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DISEASE ASSOCIATION; DISSOCIATION; DRUG MECHANISM; DRUG STRUCTURE; ENERGY TRANSFER; FLUORESCENCE POLARIZATION; HEART AMYLOIDOSIS; HEART MUSCLE CELL; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; LIGAND BINDING; MUTANT; PRIORITY JOURNAL; PROCESS DEVELOPMENT; PROPHYLAXIS; PROTEIN AGGREGATION; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN STABILITY; PROTEIN TARGETING; PROTEIN UNFOLDING; VALIDATION PROCESS; WILD TYPE;

EID: 80052071085     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3002473     Document Type: Article

References (56)

1. D. J. Selkoe, Folding proteins in fatal ways. Nature 426, 900-904 (2003).
2. F. E. Cohen, J. W. Kelly, Therapeutic approaches to protein-misfolding diseases. Nature 426, 905-909 (2003).
3. S. M. Johnson, R. L. Wiseman, Y. Sekijima, N. S. Green, S. L. Adamski-Werner, J. W. Kelly, Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: A focus on the transthyretin amyloidoses. Acc. Chem. Res. 38, 911-921 (2005).
4. H. L. Monaco, M. Rizzi, A. Coda, Structure of a complex of two plasma proteins: Transthyretin and retinol-binding protein. Science 268, 1039-1041 (1995).
5. R. H. Falk, R. L. Comenzo, M. Skinner, The systemic amyloidoses. N. Engl. J. Med. 337, 898-909 (1997).
6. L. H. Connors, A. Lim, T. Prokaeva, V. A. Roskens, C. E. Costello, Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 10, 160-184 (2003).
7. D. R. Jacobson, P. D. Gorevic, J. N. Buxbaum, A homozygous transthyretin variant associated with senile systemic amyloidosis: Evidence for a late-onset disease of genetic etiology. Am. J. Hum. Genet. 47, 127-136 (1990).
8. K. B. Shah, Y. Inoue, M. R. Mehra, Amyloidosis and the heart: A comprehensive review. Arch. Intern. Med. 166, 1805-1813 (2006).
9. H. V. Desai, W. S. Aronow, S. J. Peterson, W. H. Frishman, Cardiac amyloidosis: Approaches to diagnosis and management. Cardiol. Rev. 18, 1-11 (2010).
10. P. Westermark, K. Sletten, B. Johansson, G. G. Cornwell III, Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc. Natl. Acad. Sci. U.S.A. 87, 2843-2845 (1990).
11. C. Rapezzi, C. C. Quarta, L. Riva, S. Longhi, I. Gallelli, M. Lorenzini, P. Ciliberti, E. Biagini, F. Salvi, A. Branzi, Transthyretin-related amyloidoses and the heart: A clinical overview. Nat. Rev. Cardiol. 7, 398-408 (2010).
12. D. R. Jacobson, R. D. Pastore, R. Yaghoubian, I. Kane, G. Gallo, F. S. Buck, J. N. Buxbaum, Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N. Engl. J. Med. 336, 466-473 (1997).
13. X. Jiang, J. N. Buxbaum, J. W. Kelly, The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. Proc. Natl. Acad. Sci. U.S.A. 98, 14943-14948 (2001).
14. L. H. Connors, T. Prokaeva, A. Lim, R. Théberge, R. H. Falk, G. Doros, A. Berg, C. E. Costello, C. O'Hara, D. C. Seldin, M. Skinner, Cardiac amyloidosis in African Americans: Comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am. Heart J. 158, 607-614 (2009).
15. J. Buxbaum, A. Alexander, J. Koziol, C. Tagoe, E. Fox, D. Kitzman, Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am. Heart J. 159, 864-870 (2010).
16. Y. Sekijima, R. L. Wiseman, J. Matteson, P. Hammarstrom, S. R. Miller, A. R. Sawkar, W. E. Balch, J. W. Kelly, The biological and chemical basis for tissue-selective amyloid disease. Cell 121, 73-85 (2005).
17. P. Hammarström, F. Schneider, J. W. Kelly, Trans-suppression of misfolding in an amyloid disease. Science 293, 2459-2462 (2001).
18. P. Hammarström, R. L. Wiseman, E. T. Powers, J. W. Kelly, Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299, 713-716 (2003).
19. http://clinicaltrials.gov/ct2/show/NCT00294671
20. P. M. Kearney, C. Baigent, J. Godwin, H. Halls, J. R. Emberson, C. Patrono, Do selective cyclooxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332, 1302-1308 (2006).
21. M. Epstein, Non-steroidal anti-inflammatory drugs and the continuum of renal dysfunction. J. Hypertens. Suppl. 20, S17-S23 (2002).
22. L. J. Marnett, A. S. Kalgutkar, Cyclooxygenase 2 inhibitors: Discovery, selectivity and the future. Trends Pharmacol. Sci. 20, 465-469 (1999).
23. J. L. Wallace, Pathogenesis of NSAID-induced gastroduodenal mucosal injury. Best Pract. Res. Clin. Gastroenterol. 15, 691-703 (2001).
24. D. Mukherjee, S. E. Nissen, E. J. Topol, Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286, 954-959 (2001).
25. J. Page, D. Henry, Consumption of NSAIDs and the development of congestive heart failure in elderly patients: An underrecognized public health problem. Arch. Intern. Med. 160, 777-784 (2000).
26. J. Kirchheiner, J. Brockmöller, Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin. Pharmacol. Ther. 77, 1-16 (2005).
27. A. D. Rodrigues, Impact of CYP2C9 genotype on pharmacokinetics: Are all cyclooxygenase inhibitors the same? Drug Metab. Dispos. 33, 1567-1575 (2005).
28. P. Prapunpoj, L. Leelawatwatana, G. Schreiber, S. J. Richardson, Change in structure of the N-terminal region of transthyretin produces change in affinity of transthyretin to T4 and T3. FEBS J. 273, 4013-4023 (2006).
29. S. Connelly, S. Choi, S. M. Johnson, J. W. Kelly, I. A. Wilson, Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Curr. Opin. Struct. Biol. 20, 54-62 (2010).
30. S. L. Adamski-Werner, S. K. Palaninathan, J. C. Sacchettini, J. W. Kelly, Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J. Med. Chem. 47, 355-374 (2004).
31. R. L. Wiseman, S. M. Johnson, M. S. Kelker, T. Foss, I. A. Wilson, J. W. Kelly, Kinetic stabilization of an oligomeric protein by a single ligand binding event. J. Am. Chem. Soc. 127, 5540-5551 (2005).
32. Threshold value: mean signal of negative/positive control plus/minus three times their SD; separation band (S): difference between the positive and the negative thresholds values; dynamic range (R): difference between the positive and the negative means. Z factor (=S/R): a value between 0.5 and 1 indicates an excellent screening assay.
33. J. H. Zhang, T. D. Chung, K. R. Oldenburg, A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J. Biomol. Screen. 4, 67-73 (1999).
34. N. S. Green, T. R. Foss, J. W. Kelly, Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis. Proc. Natl. Acad. Sci. U.S.A. 102, 14545-14550 (2005).
35. J. Borgulya, H. Bruderer, K. Bernauer, G. Zürcher, M. Da Prada, Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: Synthesis and structure-activity studies. Helv. Chim. Acta 72, 952-968 (1989).
36. D. B. Trivella, L. Bleicher, L. de Castro Palmieri, H. J. Wiggers, C. A. Montanari, J. W. Kelly, L. M. Lima, D. Foguel, I. Polikarpov, Conformational differences between the wild type and V30M mutant transthyretin modulate its binding to genistein: Implications to tetramer stability and ligand-binding. J. Struct. Biol. 170, 522-531 (2010).
37. S. Leavitt, E. Freire, Direct measurement of protein binding energetics by isothermal titration calorimetry. Curr. Opin. Struct. Biol. 11, 560-566 (2001).
38. We note here that the ability of TTR to bind to two ligands complicates the analysis of our SPR data: In principle, there should be two on-rates and two off-rates for ligand binding, requiring a double-exponential model to fit the data. Because we used monoexponentials, our reported rate constants should be considered estimates for the slower of the two binding and dissociation events.
39. S. M. Johnson, S. Connelly, I. A. Wilson, J. W. Kelly, Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. J. Med. Chem. 51, 6348-6358 (2008).
40. S. Bourgault, S. Choi, J. N. Buxbaum, J. W. Kelly, J. L. Price, N. Reixach, Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs. Biochem. Biophys. Res. Commun. 410, 707-713 (2011).
41. M. M. Davidson, C. Nesti, L. Palenzuela, W. F. Walker, E. Hernandez, L. Protas, M. Hirano, N. D. Isaac, Novel cell lines derived from adult human ventricular cardiomyocytes. J. Mol. Cell. Cardiol. 39, 133-147 (2005).
42. N. Reixach, S. Deechongkit, X. Jiang, J. W. Kelly, J. N. Buxbaum, Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc. Natl. Acad. Sci. U.S.A. 101, 2817-2822 (2004).
43. S. R. Miller, Y. Sekijima, J. W. Kelly, Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. Lab. Invest. 84, 545-552 (2004).
44. E. Jonsén, O. B. Suhr, K. Tashima, E. Athlin, Early liver transplantation is essential for familial amyloidotic polyneuropathy patients' quality of life. Amyloid 8, 52-57 (2001).
45. I. M. Hamour, H. J. Lachmann, H. J. Goodman, M. Petrou, M. M. Burke, P. N. Hawkins, N. R. Banner, Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis. Am. J. Transplant. 8, 1056-1059 (2008).
46. M. R. Almeida, L. Gales, A. M. Damas, I. Cardoso, M. J. Saraiva, Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses. Curr. Drug Targets CNS Neurol. Disord. 4, 587-596 (2005).
47. S. L. McCutchen, W. Colon, J. W. Kelly, Transthyretin mutation Leu-55-Pro significantly alters tetramer stability and increases amyloidogenicity. Biochemistry 32, 12119-12127 (1993).
48. A. Quintas, M. J. Saraiva, R. M. Brito, The amyloidogenic potential of transthyretin variants correlates with their tendency to aggregate in solution. FEBS Lett. 418, 297-300 (1997).
49. I. L. Alves, K. Atland, M. R. Almeida, P. Winter, M. J. Saraiva, Screening and biochemical characterization of transthyretin variants in the Portuguese population. Hum. Mutat. 9, 226-233 (1997).
50. S. E. Kolstoe, S. P. Wood, Drug targets for amyloidosis. Biochem. Soc. Trans. 38, 466-470 (2010).
51. http://clinicaltrials.gov/ct2/show/NCT00409175, http://clinicaltrials. gov/ct2/show/NCT00791492
52. S. Yi, K. Takahashi, M. Naito, F. Tashiro, S. Wakasugi, S. Maeda, K. Shimada, K. Yamamura, S. Araki, Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene. Pathologic similarity to human familial amyloidotic polyneuropathy, type I. Am. J. Pathol. 138, 403-412 (1991).
53. K. Kohno, J. A. Palha, K. Miyakawa, M. J. Saraiva, S. Ito, T. Mabuchi, W. S. Blaner, H. Iijima, S. Tsukahara, V. Episkopou, M. E. Gottesman, K. Shimada, K. Takahashi, K. Yamamura, S. Maeda, Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy. Am. J. Pathol. 150, 1497-1508 (1997).
54. Y. Ingenbleek, V. Young, Transthyretin (prealbumin) in health and disease: Nutritional implications. Annu. Rev. Nutr. 14, 495-533 (1994).
55. A. S. Fauci, E. Braunwald, D. L. Kasper, S. L. Hauser, D. L. Longo, J. L. Jameson, J. Loscalzo, Harrison's Principles of Internal Medicine (McGraw-Hill, New York, ed. 17, 2008) pp. 1763-1770.
56. Acknowledgments: We thank D. Solow-Cordero for help with the HTS, G. Crabtree for critical reading of the manuscript, C. Garcia for use of the Biacore T100, A. Esteras-Chopo for advice, and M. Davidson for providing the AC16 cell line. Funding: This work was supported by the Hillblom Foundation (I.A.G.); NIH grants 5PN2EY016525 (I.A.G.), DK 46335 (J.W.K.), and AI 42266 (I.A.W.); AG032285 (N.R.); American Heart Association 0865061F (N.R.); and the Skaggs Institute of Chemical Biology (J.W.K. and I.A.W.). Author contributions: M.M.A. designed and performed most of the experiments. S.C. performed crystallographic structure determination. A.C. performed the serum TTR stabilization. N.R. performed the cell-based assays. E.T.P. analyzed the ITC data. D.W.P. helped with probe synthesis. I.A.W. and J.W.K. supervised the crystallographic work. I.A.G. supervised the work. S.C., N.R., I.A.W., and J.W.K. edited the paper. M.M.A. and I.A.G. prepared the manuscript. Competing interests: J.W.K. is a co-founder, shareholder, and paid consultant for two biotechnology companies, FoldRx Pharmaceuticals Inc. (now Pfizer) and Proteostasis Therapeutics Inc., which specialize in the discovery and development of drug therapies for diseases of protein misfolding and amyloidosis. The other authors declare that they have no competing interests. Stanford University has filed a patent application for the FP assay and for the compounds that are described in the manuscript. Accession codes: Atomic coordinates have been deposited in the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank and are available under accession codes 3P3R (Ro-41-0960), 3P3S (14), 3P3T (7), and 3P3U (9).