Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir.,ACS Chemical Biology

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Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-01-08 , DOI: 10.1021/acschembio.9b00675
Jennifer Timm ₁ , Klajdi Kosovrasti ₁ , Mina Henes ₁ , Florian Leidner ₁ , Shurong Hou ₁ , Akbar Ali ₁ , Nese Kurt Yilmaz ₁ , Celia A Schiffer ₁

Affiliation

Hepatitis C virus, causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68 to 82%. While older generation direct-acting antivirals had varying effectiveness against different genotypes, the newest NS3/4A protease inhibitors including glecaprevir (GLE) have pan-genotypic activity. The structural basis for pan-genotypic inhibition and effects of polymorphisms on inhibitor potency were not well-known due to lack of crystal structures of GLE-bound NS3/4A or genotypes other than 1. In this study, we determined the crystal structures of NS3/4A from genotypes 1a, 3a, 4a, and 5a in complex with GLE. Comparison with the highly similar grazoprevir indicated the mechanism of GLE's drastic improvement in potency. We found that, while GLE is highly potent against wild-type NS3/4A of all genotypes, specific resistance-associated substitutions (RASs) confer orders of magnitude loss in inhibition. Our crystal structures reveal molecular mechanisms behind pan-genotypic activity of GLE, including potency loss due to RASs at D168. Our structures permit for the first time analysis of changes due to polymorphisms among genotypes, providing insights into design principles that can aid future drug development and potentially can be extended to other proteins.

中文翻译：

Glecaprevir 抑制泛基因型 HCV NS3/4A 蛋白酶的分子和结构机制。

丙型肝炎病毒是慢性病毒性肝炎的病原体，感染全世界7100万人，分为七种基因型和多种亚型，序列同一性在68%至82%之间。虽然老一代直接作用抗病毒药物针对不同基因型的疗效各不相同，但包括 glecaprevir (GLE) 在内的最新 NS3/4A 蛋白酶抑制剂具有泛基因型活性。由于缺乏 GLE 结合的 NS3/4A 的晶体结构或 1 以外的基因型，泛基因型抑制的结构基础以及多态性对抑制剂效力的影响尚不清楚。在本研究中，我们确定了 NS3 的晶体结构/4A 来自与 GLE 复合的基因型 1a、3a、4a 和 5a。与高度相似的grazoprevir的比较表明了GLE显着提高药效的机制。我们发现，虽然 GLE 对所有基因型的野生型 NS3/4A 都非常有效，但特异性耐药相关取代 (RAS) 会导致抑制作用降低几个数量级。我们的晶体结构揭示了 GLE 泛基因型活性背后的分子机制，包括 D168 处 RAS 导致的效力损失。我们的结构首次允许分析基因型之间多态性引起的变化，提供对设计原则的见解，这些原则可以帮助未来的药物开发，并有可能扩展到其他蛋白质。

更新日期：2020-01-08

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