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Small-molecule effectors of hepatitis B virus capsid assembly give insight into virus life cycle.

Authors
  • Bourne, Christina
  • Lee, Sejin
  • Venkataiah, Bollu
  • Lee, Angela
  • Korba, Brent
  • Finn, M G
  • Zlotnick, Adam
Type
Published Article
Journal
Journal of Virology
Publisher
American Society for Microbiology
Publication Date
Oct 01, 2008
Volume
82
Issue
20
Pages
10262–10270
Identifiers
DOI: 10.1128/JVI.01360-08
PMID: 18684823
Source
Medline
License
Unknown

Abstract

The relationship between the physical chemistry and biology of self-assembly is poorly understood, but it will be critical to quantitatively understand infection and for the design of antivirals that target virus genesis. Here we take advantage of heteroaryldihydropyrimidines (HAPs), which affect hepatitis B virus (HBV) assembly, to gain insight and correlate in vitro assembly with HBV replication in culture. Based on a low-resolution crystal structure of a capsid-HAP complex, a closely related series of HAPs were designed and synthesized. These differentially strengthen the association between neighboring capsid proteins, alter the kinetics of assembly, and give rise to aberrant structures incompatible with a functional capsid. The chemical nature of the HAP variants correlated well with the structure of the HAP binding pocket. The thermodynamics and kinetics of in vitro assembly had strong and predictable effects on product morphology. However, only the kinetics of in vitro assembly had a strong correlation with inhibition of HBV replication in HepG2.2.15 cells; there was at best a weak correlation between assembly thermodynamics and replication. The correlation between assembly kinetics and virus suppression implies a competition between successful assembly and misassembly, small molecule induced or otherwise. This is a predictive and testable model for the mechanism of action of assembly effectors.

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