# HBV Capsid Effectors

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $702,799

## Abstract

PROJECT SUMMARY/ABSTRACT
 Despite the availability of an effective vaccine, epidemiologic data estimates about 2 billion people globally
are infected with hepatitis B virus (HBV). Approximately 350 million people are chronic HBV carriers and at high
risk for the development of hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Current anti-HBV treatment
options suppress the virus but do not eliminate the virus, requiring costly lifetime therapy. All FDA approved
therapeutic approaches fail to target the HBV covalently closed-circular DNA (cccDNA; associated with viral
persistence) or the virus capsid which is essential for virus proliferation. Our approach in this application is to
target capsid assembly, which is essential for replication, as DNA synthesis from cccDNA occurs exclusively
within the capsid encoded particle. HBV core proteins (Cp) constitute the subunits in viral capsid assembly and
Capsid Assembly Modulators (CAM) accelerate the kinetics of capsid assembly whereby they prevent pol-
pgRNA complex encapsidation and block HBV replication. CAMs also interfere with cccDNA transcription/de
novo formation during early steps of infection. As part of our ongoing HBV CAM discovery program NIH-
supported over the last 4 years, we have been successful in developing several highly potent (sub-micromolar)
class II CAMs with one of our lead compounds entering phase 1 clinical trials in October 2020. However, there
are numerous hurdles that could derail our efforts towards FDA approval. Here, we describe for the first time a
novel class of homo or hetero-dimer CAM displaying selective anti-HBV activity in culture in the picomolar range.
Because a dimeric structure linking two CAM moieties can interact with two distinct sites of one capsid or
eventually connect two (or more) capsids together, we hypothesized that these compounds would have a more
profound impact on HBV capsid assembly than known class I or II CAMs. Based on the potency and the unique
mode of action (MoA) we termed our new compounds as “class III” CAMs. We propose to evaluate these class
III CAMs by pursuing three specific aims: 1) To chemically optimize and characterize a unique series of CAM
homo/heterodimers made from novel monomers; 2) To characterize (structurally, biochemically, and biologically)
novel CAM homo/heterodimer binding interaction with HBV capsid; 3) To determine pharmacokinetics (PK) and
in vivo efficacy of novel CAM homo and heterodimers. Novel homo and heterodimers will be synthesized and
evaluated to reach maximum potency and drug-like properties. To differentiate our compounds from existing
class I and II CAMs, we will characterize structural and dynamical effects of our new CAMs by determining a)
their effect on the morphology of HBV capsids and their localization within cells, b) binding to HBV wild-type and
known mutant Cp, c) resistance profile and activity against major CAM resistant HBV strains and d) intra- or
inter-capsid connections. Results fr...

## Key facts

- **NIH application ID:** 10594522
- **Project number:** 5R01AI132833-06
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Raymond Felix Schinazi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $702,799
- **Award type:** 5
- **Project period:** 2017-06-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10594522

## Citation

> US National Institutes of Health, RePORTER application 10594522, HBV Capsid Effectors (5R01AI132833-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10594522. Licensed CC0.

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