Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity.
Potent kinetic stabilizers that prevent transthyretin-mediated cardiomyocyte proteotoxicity.
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DOI：
10.1126/scitranslmed.3002473
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发表时间：
2011-08-24
影响因子：
17.1
通讯作者：
Graef IA
中科院分区：
文献类型：
--
作者：
Alhamadsheh MM;Connelly S;Cho A;Reixach N;Powers ET;Pan DW;Wilson IA;Kelly JW;Graef IA
V122 I突变改变了甲状腺素运载蛋白（TTR）的稳定性，影响3-4%的非洲裔美国人，并导致淀粉样蛋白生成和心肌病的发展。此外，10-15%的65岁以上的个体由于野生型TTR淀粉样蛋白生成而发展成老年系统性淀粉样变性（SSA）和心脏TTR沉积。由于没有批准的TTR淀粉样心肌病的治疗方法，因此需要开发预防淀粉样蛋白介导的心脏毒性的药物。为此，我们开发了一种基于荧光偏振的HTS筛选，确定了几种新的靶向TTR的化学支架。这些新化合物是TTR的有效动力学稳定剂，并防止野生型和最常见的心肌病相关TTR突变体V122 I-TTR的四聚体解离、解折叠和聚集。高分辨率的共晶结构和结合能的表征揭示了这些不同的结构如何与四聚体TTR结合。我们的研究还表明，这些化合物有效地抑制V122 I-TTR对人心肌细胞的蛋白毒性。这些配体中的几种比二氟尼柳更有效地稳定人血清中的TTR，二氟尼柳是TTR聚集的最佳已知抑制剂之一，并且可能是治疗和/或预防TTR介导的心肌病的有希望的线索。
The V122I mutation that alters the stability of transthyretin (TTR) affects 3–4% of African Americans and leads to amyloidogenesis and development of cardiomyopathy. In addition, 10–15% of individuals over the age of 65 develop senile systemic amyloidosis (SSA) and cardiac TTR deposits due to wild-type TTR amyloidogenesis. As no approved therapies for TTR amyloid cardiomyopathy are available, the development of drugs that prevent amyloid-mediated cardiotoxicity is desired. To this aim, we developed a fluorescence polarization-based HTS screen, which identified several new chemical scaffolds targeting TTR. These novel compounds were potent kinetic stabilizers of TTR and prevented tetramer dissociation, unfolding and aggregation of both wild type and the most common cardiomyopathy-associated TTR mutant, V122I-TTR. High-resolution co-crystal structures and characterization of the binding energetics revealed how these diverse structures bound to tetrameric TTR. Our study also showed that these compounds effectively inhibited the proteotoxicity of V122I-TTR towards human cardiomyocytes. Several of these ligands stabilized TTR in human serum more effectively than diflunisal, which is one of the best known inhibitors of TTR aggregation, and may be promising leads for the treatment and/or prevention of TTR-mediated cardiomyopathy.
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影响因子：
6.7
作者：
Kirchheiner, J;Brockmöller, J
通讯作者：
Brockmöller, J
影响因子：
4.8
作者：
Buxbaum, Joel;Alexander, Alice;Kitzman, Dalane
通讯作者：
Kitzman, Dalane
DOI：
10.2174/156800705774322076
发表时间：
2005-10-01
期刊：
Current Drug Targets - CNS and Neurological Disorders
影响因子：
--
作者：
Almeida, M. R.;Gales, L.;Saraiva, M. J.
通讯作者：
Saraiva, M. J.
DOI：
10.1073/pnas.0501609102
发表时间：
2005-10-11
影响因子：
11.1
作者：
Green, NS;Foss, TR;Kelly, JW
通讯作者：
Kelly, JW
影响因子：
8.8
作者：
Hamour, I. M.;Lachmann, H. J.;Banner, N. R.
通讯作者：
Banner, N. R.