Kazmierski Wieslaw M, Miriyala Nagaraju, Johnson David K, Baskaran Sam
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
Computational Chemical Biology Core and Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, Kansas 66047, United States.
ACS Med Chem Lett. 2021 Sep 15;12(11):1649-1655. doi: 10.1021/acsmedchemlett.1c00391. eCollection 2021 Nov 11.
HCV NS5A inhibitors are the backbone of directly acting antiviral treatments against the hepatitis C virus (HCV). While these therapies are generally highly curative, they are less effective in some specific HCV patient populations. In the search for broader-acting HCV NS5A inhibitors that address these needs, we explored conformational restrictions imposed by the [7,5]-azabicyclic lactam moiety incorporated into daclatasvir () and related HCV NS5A inhibitors. Unexpectedly, compound was identified as a potent HCV genotype 1a and 1b inhibitor. Molecular modeling of bound to HCV genotype 1a suggested that the use of the conformationally restricted lactam moiety might have resulted in reorientation of its N-terminal carbamate to expose a new interaction with the NS5A pocket located between amino acids P97 and Y93, which was not easily accessible to . The results also suggest new chemistry directions that exploit the interactions with the P97-Y93 site toward new and potentially improved HCV NS5A inhibitors.
丙型肝炎病毒（HCV）NS5A抑制剂是抗丙型肝炎病毒直接抗病毒治疗的核心药物。虽然这些疗法通常具有很高的治愈率，但在某些特定的HCV患者群体中效果较差。为了寻找能够满足这些需求的更具广泛活性的HCV NS5A抑制剂，我们研究了达卡他韦（）及相关HCV NS5A抑制剂中[7,5]-氮杂双环内酰胺部分所带来的构象限制。出乎意料的是，化合物被鉴定为一种有效的HCV 1a和1b基因型抑制剂。与HCV 1a基因型结合的分子模型表明，使用构象受限的内酰胺部分可能导致其N-末端氨基甲酸酯重新定向，从而暴露出与位于氨基酸P97和Y93之间的NS5A口袋的新相互作用，而这种相互作用对于来说并不容易实现。结果还表明了新的化学方向，即利用与P97 - Y93位点的相互作用来开发新的、可能更有效的HCV NS5A抑制剂。
