Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
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DOI：
10.1038/s41467-019-11429-w
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发表时间：
2019-08-01
影响因子：
16.6
通讯作者：
Yang, Priscilla L.
中科院分区：
文献类型：
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作者：
de Wispelaere, Melissanne;Du, Guangyan;Yang, Priscilla L.
靶向蛋白质降解是一种很有前途的药物开发范例。在这里，我们利用这一策略来开发一类新的小分子抗病毒药物，它可以诱导病毒蛋白的蛋白酶体降解。Telaprevir是一种可逆的共价抑制剂，与丙型肝炎病毒(HCV)蛋白酶活性部位结合，连接到招募CRL4(CRBN)连接酶复合体的配体上，产生既能抑制又能诱导丙型肝炎病毒NS3/4A蛋白酶降解的化合物。一个优化的降解剂，DGY-08-097，在细胞感染模型中有效地抑制了丙型肝炎病毒，我们证明了蛋白质降解有助于其抗病毒活性。最后，我们证明了这类新的抗病毒药物可以克服病毒变异，这些病毒变异赋予了对传统酶抑制剂如替瑞韦的耐药性。总体而言，我们的工作提供了概念证明，即靶向蛋白质降解可能为开发具有优越耐药性特征的抗病毒药物提供一个新的范例。
Targeted protein degradation is a promising drug development paradigm. Here we leverage this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a reversible-covalent inhibitor that binds to the hepatitis C virus (HCV) protease active site is conjugated to ligands that recruit the CRL4(CRBN) ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.