Negative cooperativity drives activity of capsid-directed antivirals against hepatitis B virus
Hepatitis B virus capsid protein plays a role in almost every step of viral replication, from self-assembly to genome release. This makes capsid protein an attractive target for antiviral development. Capsid assembly modulators (CAMs) are direct-acting antivirals that bind capsid protein, leading to empty or aberrant complexes instead of an infectious virus. CAMs can also disrupt the capsid, preventing new infection. To understand CAM activity, we examined the energetics of CAM-capsid interaction. We observed negative cooperativity of CAM-binding kinetics and thermodynamics. These correlate with large changes in capsid architecture that presage capsid rupture. We propose that CAMs induce an accumulated strain on the capsid. Understanding the interplay of forces and architecture will help guide the development of CAMs.
Authors
- Smita Nair (ORCID: https://orcid.org/0000-0002-2983-3597)
- Irina B. Tsvetkova (ORCID: https://orcid.org/0000-0002-3433-328X)
- Samson Francis
- VanNieuwenhze Michael
- Joseph Che‐Yen Wang (ORCID: https://orcid.org/0000-0001-6580-3531)
- Balasubramanian Venkatakrishnan (ORCID: https://orcid.org/0000-0003-3818-1284)
- Shiv Kumar (ORCID: https://orcid.org/0000-0003-0655-9561)
- Adam Zlotnick (ORCID: https://orcid.org/0000-0001-9945-6267)
- Nora Gibes
- Angela Patterson
- Caleb J. Valkner
- Bogdan Dragnea (ORCID: https://orcid.org/0000-0003-0611-2006)
- Marina Sicheng Xie (ORCID: https://orcid.org/0000-0002-3603-622X)
Institutions
- Pennsylvania State University (US)
- Indiana University Bloomington (US)
- WisdomTools (United States) (US)
- Penn State Milton S. Hershey Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-06-12
- DOI
- https://doi.org/10.1126/sciadv.aed6483
- Primary Topic
- Bacteriophages and microbial interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute of Allergy and Infectious Diseases