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Hepatitis C virus NS5A inhibitor daclatasvir allosterically impairs NS4B-involved protein-protein interactions within the viral replicase and disrupts the replicase quaternary structure in a replicase assembly surrogate system

By Yang Zhang, Jingyi Zou, Xiaomin Zhao, Zhenghong Yuan, Zhigang Yi

Posted 31 May 2018
bioRxiv DOI: 10.1101/335273 (published DOI: 10.1099/jgv.0.001180)

Daclatasvir (DCV) is a highly potent direct-acting antiviral that targets the non-structural protein 5A (NS5A) of hepatitis C virus (HCV) and has achieved great clinical successes. Previous studies demonstrate its impact on the viral replication complex assembly. However the precise mechanism by which DCV impairs the replication complex assembly remains elusive. In this study, by using HCV subgenomic replicons and a viral replicase assembly surrogate system that expresses the HCV NS3-5B polyprotein to mimic the viral replicase assembly, we dissected the impacts of DCV on aggregation and tertiary structure of NS5A, the protein-protein interactions within the viral replicase and the quaternary structure of the viral replicase. We found that DCV didn't affect aggregation and tertiary structure of NS5A. DCV induced a quaternary structural change of the viral replicase, evidenced by selectively increasing of the NS4B's sensitivity to proteinase K digestion. Mechanically, DCV impaired the NS4B-involved protein-protein interactions within the viral replicase. The DCV-resistant mutant Y93H was refractory to the DCV-induced reduction of the NS4B-invoved protein interactions and the quaternary structural change of the viral replicase. In addition, Y93H reduced NS4B-involed protein-protein interactions within the viral replicase and attenuated viral replication. We propose that DCV may induce a position change of NS5A, which allosterically affects the protein interactions within the replicase components and disrupts the replicase assembly.

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