Translational development of a small molecule for the treatment of HBV infection

The National Institute of Allergy and Infectious Diseases awarded Jericho Sciences, LLC $635,226 on September 22, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop a small molecule therapeutic targeting hepatitis B virus infection.

The project aims to validate and advance a novel small molecule drug candidate that targets the hepatitis B X regulatory protein (HBX), a critical protein involved in the persistence of covalently closed circular DNA (cccDNA)—the viral reservoir that persists despite current antiviral therapies and drives ongoing replication and drug resistance. Work includes laboratory research, analytical method development, formulation studies, and preclinical validation. Preliminary in vitro studies demonstrate concentration-dependent inhibition of HBX-mediated depletion of SMC5/6 complex proteins, a key mechanism of viral persistence.

The award is structured as a Small Business Technology Transfer (STTR) Phase I grant, bringing together expertise in HBV molecular biology and antiviral drug discovery. Performance occurs in Durham, North Carolina, with a period of performance through August 31, 2027. The project addresses the clinical challenge that approximately 300 million individuals worldwide carry chronic HBV infection despite available vaccines and current antivirals, with elevated risks of cirrhosis, liver failure, and hepatocellular carcinoma.

Abstract

Chronic hepatitis b virus (HBV) infection remains a substantial global public health burden despite the availability of vaccines and antiviral therapies, impacting approximately 300 million individuals worldwide. The virus infects hepatocytes, leading to significant morbidity and mortality implications, including increased risks of cirrhosis, liver failure, and hepatocellular carcinoma. Organizations such as the world health organization (who) and the national institutes of health (NIH) aspire to develop a cure for HBV, projected to save thousands of lives and reduce economic burdens associated with liver transplants and chronic disease management. A key challenge to curing chronic HBV infection is the persistence of an independent, viral, covalently closed circular DNA (cccdna) minichromosome in the nucleus of infected hepatocytes, which serves as a reservoir for ongoing viral replication and viral antigen expression. Current antiviral therapies, such as nucleos(t)IDE reverse transcriptase inhibitors (NAS) and interferon-α (IFN-α), are inadequate to eliminate cccdna or reduce viral antigenemia, leading to viral rebound and drug resistance. There is urgency for novel therapeutic approaches targeting HBV cccdna longevity and/or transcriptional activities that will help clear chronic infection. This sttr application brings together experts in HBV molecular biology and antiviral discovery to advance the development of a novel small molecule therapeutic intervention. Through collaborative efforts including laboratory research, analytical method development, formulation and preclinical studies, this project will validate the proposed drug target, hepatitis b x regulatory protein (HBX), a multifunctional critical player in HBV cccdna epigenetics and transcription. Our preliminary in vitro studies demonstrate concentration-dependent inhibition of HBX-mediated depletion of SMC5/6 (a well-acknowledged cellular silencer of cccdna) and suppression of cccdna transcription in HBV-infected cells, supporting the prospect of a new drug class. Our phase i project comprises two specific aims: (1) in vitro characterization of antiviral activities associated with targeting HBX and cccdna in multiple cell models to discern the implications of potential viral clearance mechanisms, and (2) in vivo pharmacokinetic and pharmacodynamic studies in a rodent model to optimize drug formulation and dosing routes that support safe and effective drug delivery to target liver tissues. Successful completion of these aims will enable subsequent proof-of-concept phase II HBV-infected humanized mouse model studies and advance preclinical development for IND-enabling milestones toward clinical testing. This project enables an innovative therapeutic approach − defined as a high strategic priority by both the NIH and the who − to develop curative therapies for chronic HBV infection, which could significantly impact public health outcomes and reduce the global burden of this disease.