# Development of a New Class of Hepatitis B Virus Inhibitors that Induce a Novel Defective Nucleocapsid Phenotype

> **NIH NIH R43** · MICROBIOTIX, INC · 2021 · $298,323

## Abstract

Summary:
Hepatitis B virus (HBV) is a small DNA virus that chronically infects 240 million people worldwide,
resulting in over 650 thousand deaths annually. HBV-induced fatalities typically result from a
variety of severe liver pathologies including cirrhosis, hepatocellular carcinoma and liver failure.
The current standard of care for chronic HBV infection uses viral DNA polymerase inhibitors or
immunomodulators (interferons) that reduces viral loads and prevents progression of liver
disease, but rarely induces a functional cure, with recurrence occurring nearly universally
following cessation of treatment. The failure to achieve a functional cure is attributed to the
persistence of viral covalently closed circular DNA (cccDNA) pools in infected liver cells that is
neither suppressed nor eliminated by these therapies. Accordingly, there is a critical need for new
HBV therapeutics targeting multiple stages of the viral lifecycle which can affect these cccDNA
pools. We have discovered a new Type of HBV core protein allosteric modulators (CpAMs),
exemplified by MBX-6035, that disrupt capsid assembly through a unique phenotype. Analysis of
MBX-6035 analogs revealed responsive SAR and included analogs that are potent (EC50 as low
as 1.3 µM), selective (>100-fold SI), soluble (up to 400 µM), minimally protein bound (>30%
unbound in murine plasma), and metabolically stable (t1/2 >100 min in murine liver microsomes),
strongly justifying further pursuit of this novel series. Our strategy in this Phase I proposal is to
optimize the potency and drug-like properties of this series to generate lead compounds suitable
for further development and demonstration of in vivo efficacy in a future Phase II application.

## Key facts

- **NIH application ID:** 10220712
- **Project number:** 5R43AI155192-02
- **Recipient organization:** MICROBIOTIX, INC
- **Principal Investigator:** Zachary David Aron
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $298,323
- **Award type:** 5
- **Project period:** 2020-07-21 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220712

## Citation

> US National Institutes of Health, RePORTER application 10220712, Development of a New Class of Hepatitis B Virus Inhibitors that Induce a Novel Defective Nucleocapsid Phenotype (5R43AI155192-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10220712. Licensed CC0.

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