Redesigning HBV assembly capsid modulators to induce apoptosis

The National Institute of Allergy and Infectious Diseases awarded $232,737 to the Trustees of Indiana University on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to redesign hepatitis B virus capsid assembly modulators that induce apoptosis in infected cells.

The research addresses the absence of a cure for chronic HBV despite available reverse transcriptase inhibitor treatments that control but do not eliminate the virus. The project targets the viral capsid protein, which plays a critical role throughout the HBV replication cycle—from packaging viral RNA to intracellular trafficking and maintaining infection. The recipient will develop improved capsid assembly modulators (CAMs) that accelerate abnormal assembly, preventing formation of infectious particles and accumulating capsid complexes in the nucleus of infected cells to trigger apoptosis. The hypothesis is that clearing infected hepatocytes through apoptosis could allow replacement with healthy newly divided cells, potentially establishing a functional cure. Current apoptosis-driving CAMs are slow-acting and require high intracellular concentrations; the project applies structure-guided medicinal chemistry approaches to design modulators with improved potency and kinetics.

Performance occurs in Bloomington, Indiana, with period of performance from September 1, 2026 through August 31, 2028. The award is classified as a Project Grant under the assistance type.

Abstract

Hepatitis b virus (HBV) is a global health burden that also deeply impacts the united states. Globally, more than 300 million people suffer from chronic HBV; in the united states as many as 2 million individuals have chronic HBV. Chronic HBV can lead to liver failure, cirrhosis, and hepatocellular carcinoma. Treatments (i.e. reverse transcriptase inhibitors) can control HBV, but there is no cure. HBV is a very small virus encoding only four proteins, and the capsid protein plays a role at almost every step of the viral replication cycle. Capsid protein activities include packaging viral RNA, serving as a compartment for reverse transcription, intracellular trafficking to either the ER (to pick up an envelope) or the nucleus (to maintain infection). Many strategies are being tested in the effort to develop a functional cure for chronic HBV. Because of its importance to virus function, one of the most attractive experimental approaches to a functional cure is capsid assembly modulators (cams). The best characterized activity of capsid protein is its ability to assemble into icosahedral capsids. Cams are agonists of the assembly reaction. They accelerate assembly by binding at a protein-protein interface to strengthen association and also favor an assembly active conformation. The result is empty or aberrant complexes instead of the RNA-filled particles needed to make more virus. A subset of cams that induce aberrant assembly lead to large capsid protein complexes that accumulate in the nucleus of an infected cell and lead to apoptosis. Apoptosis could hypothetically clear the liver of infected cells and promote their replacement with healthy newly divided hepatocytes. However, apoptosis driving cams are slow to act and require relatively high intracellular concentrations of capsid protein. In this proposal we take three aims towards building a better cam. Aim 1: we use structure-guided medicinal chemistry to redesign cams for aberrant assembly and improved assembly energetics. Aim 2: we examine the biophysics of cam-induced assembly to ensure that our compounds are inducing aberrant assembly. Aim 3: we use a series of cell culture assays for antiviral activities. In this proposal we will identify the features of cam-protein interactions that most correlate with different antiviral activities. In the larger picture, this proposal will contribute to developing cams and testing their ability to lead to a functional cure for chronic HBV.