Negative cooperativity drives activity of capsid-directed antivirals against hepatitis B virus

  • Sci Adv. 2026 Jun 12;12(24):eaed6483. doi: 10.1126/sciadv.aed6483.
Caleb J Valkner  1 ,  Nora Gibes  1 ,  Marina Sicheng Xie  2 ,  Smita Nair  3 ,  Shiv Kumar  4 ,  Samson Francis  1 ,  Balasubramanian Venkatakrishnan  1 ,  Irina Tsvetkova  2 ,  Angela Patterson  1 ,  Michael VanNieuwenhze  2 ,  Bogdan Dragnea  2 ,  Joseph Che-Yen Wang  4 ,  Adam Zlotnick  1
Affiliations
  • 1. Molecular and Cellular Biochemistry Department, Indiana University-Bloomington, Bloomington, IN 47405, USA.
  • 2. Chemistry Department, Indiana University-Bloomington, Bloomington, IN 47405, USA.
  • 3. Door Pharmaceuticals LLC, Bloomington, IN 47405, USA.
  • 4. Department of Cell and Biological Systems, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
PMID: 42284399 DOI: 10.1126/sciadv.aed6483
Abstract

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.

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