Local Stabilization of Subunit-Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids

Christopher John Schlicksup, Patrick Laughlin, Steven Dunkelbarger, Joseph Che Yen Wang, Adam Zlotnick

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Development of antiviral molecules that bind virion is a strategy that remains in its infancy, and the details of their mechanisms are poorly understood. Here we investigate the behavior of DBT1, a dibenzothiazepine that specifically interacts with the capsid protein of hepatitis B virus (HBV). We found that DBT1 stabilizes protein-protein interaction, accelerates capsid assembly, and can induce formation of aberrant particles. Paradoxically, DBT1 can cause preformed capsids to dissociate. These activities may lead to (i) assembly of empty and defective capsids, inhibiting formation of new virus, and (ii) disruption of mature viruses, which are metastable, to inhibit new infection. Using cryo-electron microscopy, we observed that DBT1 led to asymmetric capsids where well-defined DBT1 density was bound at all intersubunit contacts. These results suggest that DBT1 can support assembly by increasing buried surface area but induce disassembly of metastable capsids by favoring asymmetry to induce structural defects.

Original languageEnglish (US)
Pages (from-to)1708-1717
Number of pages10
JournalACS chemical biology
Volume15
Issue number6
DOIs
StatePublished - Jun 19 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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