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The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.<\/jats:p>","DOI":"10.1073\/pnas.1300761110","type":"journal-article","created":{"date-parts":[[2013,5,29]],"date-time":"2013-05-29T01:46:29Z","timestamp":1369791989000},"page":"9992-9997","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":186,"title":["AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin"],"prefix":"10.1073","volume":"110","author":[{"given":"Sravan C.","family":"Penchala","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Connelly","sequence":"additional","affiliation":[{"name":"Departments of bIntegrative Structural and Computational Biology and"},{"name":"Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki S.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Baranczak","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irit","family":"Rappley","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Liedtke","sequence":"additional","affiliation":[{"name":"Department of Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald M.","family":"Witteles","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan T.","family":"Powers","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e0lia","family":"Reixach","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William K.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Departments of bIntegrative Structural and Computational Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery W.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella A.","family":"Graef","sequence":"additional","affiliation":[{"name":"Department of Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoun M.","family":"Alhamadsheh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,5,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/nature02264","article-title":"Folding proteins in fatal ways","volume":"426","author":"Selkoe DJ","year":"2003","unstructured":"DJ Selkoe, Folding proteins in fatal ways. 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