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Title: The Mechanism of Action of Hepatitis B Virus Capsid Assembly Modulators Can Be Predicted from Binding to Early Assembly Intermediates
Award ID(s):
1828187
NSF-PAR ID:
10398107
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ;
Date Published:
Journal Name:
Journal of Medicinal Chemistry
Volume:
65
Issue:
6
ISSN:
0022-2623
Page Range / eLocation ID:
4854 to 4864
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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  1. Interfering with the self-assembly of virus nucleocapsids is a promising approach for the development of novel antiviral agents. Applied to hepatitis B virus (HBV), this approach has led to several classes of capsid assembly modulators (CAMs) that target the virus by either accelerating nucleocapsid assembly or misdirecting it into non-capsid-like particles. Here, we have assessed the structures of early nucleocapsid assembly intermediates, with and without bound CAMs, using molecular dynamics simulations. We find that distinct conformations of the intermediates are induced depending on whether the bound CAM accelerates or misdirects assembly; these structures are predictive of the final assembly. We also selected non-capsid-like structures from our simulations for virtual screening, resulting in the discovery of several compounds with moderate anti-viral activity and low toxicity. Cryo-electron microscopy and capsid melting experiments suggest that our compounds possess a novel mechanism for assembly modulation, potentially opening new avenues for HBV inhibition. 
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