Anti-Hepatitis B Virus (HBV) Therapeutics

Proposal for collaborative development of polymerase inhibitors based on the three-dimensional structure of HBV polymerase

Advantages

  • Completely different mechanism of action from existing drugs such as interferon and nucleic acid analogs
  • In vivo anti-HBV efficacy has been demonstrated with inhibitor candidates identified in preliminary screening
  • World’s first successful purification and crystallization of the HBV polymerase RT domain enables discovery and development of new lead compounds

Background and Technology

In the early 2000s, it was estimated that 2 billion people were transiently infected with HBV, and it is estimated that there are 300 million people worldwide who are persistently infected, that is, those who have not eliminated the virus and are still living with it. Interferon and NRTIs (reverse transcriptase inhibitors based on nucleos(t)ide analogs) have been used to treat HBV, but their side effects and drug resistance have led to calls for the development of drugs with alternative mechanisms of action.

Non-nucleos(t)ide reverse transcriptase (polymerase) inhibitors (NNRTIs) bind to HBV polymerase and directly inhibit its activity, which has a completely different mechanism of action from that of NRTIs and is expected to have a strong viral suppression effect. However, NNRTIs have not been developed so far because of the difficulty in HBV polymerase purification.

We have purified the RT domain of HBV polymerase to a high purity and succeeded in its crystallization for the first time in the world. We also identified several candidate inhibitors by preliminary screening using purified RT and confirmed their anti-HBV therapeutic effects using human hepatocyte chimeric mice.

Reference

Principal Investigator

Keiji Ueda, Prof.
(Department of Microbiology and Immunology, Osaka University Graduate School of Medicine)

Current Stage and Expectations for Partnering

[Current Stage]

  • Succeeded in purification of RT domain and constructed cell-free and cell-based assays.
  • Screened compounds from 74,000 compounds using the above assays were evaluated in human hepatocyte chimeric mice and their antiviral effects and no toxicities were confirmed.
  • Succeeded in crystallization of the purified RT domain, and is currently conducting crystal structure analysis and simulation to predict binding sites and drug combination effects.

[Expectations for Partnering]

  • Using the above data and assays, we would like to work with a partner on screening, design and development of druggable seed/lead compounds. We are looking for the partner.
  • We would like to discuss how to handle the results obtained through the collaboration on the premise that they will be shared.

 

Product number: DA-04337

Medicine

Published

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