# NIH grant: Characterization of potent antivirals targeting HBV capsid (1R21AI199669-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R21AI199669-01)

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NIH grant 1R21AI199669-01: Characterization of potent antivirals targeting HBV capsid
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Karen A Kirby. Award: $249225.
Start: 2026-06-23T00:00:00.
PROJECT SUMMARY
 Despite the availability of vaccines, Hepatitis B Virus (HBV) infection continues to be a global health issue,
with more than 295 million people infected worldwide. HBV infection can result in chronic liver disease and
hepatocellular carcinoma. Current treatments for HBV include nucleoside reverse transcriptase (RT) inhibitors
(NRTIs), which target the viral RT enzyme, and immunotherapy involving interferon alpha (IFN-α), which can be
toxic. Neither of these treatments affects the stubbornly persistent covalently closed circular (ccc)DNA, which is
considered to be a target for HBV eradication. Thus, treatment for HBV infection is life-long and continues to be
a worldwide economic burden. Antivirals targeting additional steps of the HBV replication cycle that can eliminate
cccDNA are needed toward achieving a functional cure. One such target is the HBV nucleocapsid or capsid,
which plays a critical role during several stages of HBV replication. Several compounds have been discovered
and have demonstrated the ability to block viral replication by affecting the assembly of HBV Core protein (Cp)
into the icosahedral capsid. These compounds are referred to as capsid assembly modulators, or CAMs. Over
the years, two main classes of CAMs have been studied: class I CAMs or CAM-As that upon binding to HBV
capsids promotes their misassembly into aberrant non-capsid polymers; and class II CAMs or CAM-Es that upon
binding to the capsid form normal, but empty, nonfunctional capsids. Recently, another novel type of antivirals
that comprise two CAMs connected by a linker (termed as bivalent CAMs) have also been identified as highly
potent (sub-nanomolar) anti-HBV compounds. It is not yet understood how this new class of compounds affects
HBV capsid assembly and structure. We hypothesize that bivalent CAMs cause distinct structural changes and
lattice deformations of HBV capsids that result in a unique mechanism of action. The following specific aims will
address our hypothesis:
Aim 1. Native mass spectrometry (nMS) characterization of bivalent CAMs.
Aim 2. Novel single particle cryo-EM characterization of bivalent CAM-treated HBV capsids.
 Overall, these experiments should address major knowledge gaps by providing valuable insights into the MOA
of bivalent CAMs to promote their advancement to clinical studies. These studies will also provide information
on possibilities for future novel CAM-based combination therapies toward the goal of HBV eradication and cure.
```



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