SBIR-STTR Award

Hepatoselective Dihydroquinolizinone (HS-HS-DHQ) Molecules for Treatment and Prevention of Hepatitis A Virus InfectionThis is a Phase I proposal to develop Harlingene's hepatoselective dihydroquinolizinones (HS-DHQs) for treatment and prevention of hepatitis A virus (HAV) infection. This will be the firstantiviral therapy to treat HAV infection, which, despite vaccines to prevent disease, causesthousands of hospitalizations and many deaths each year in the U.S. DHQs, exemplified by theRoche compound, RG7834, have been shown to be effective antivirals for hepatitis B virus (HBV)and have been under development for HBV by a number of small and major pharmaceuticalcompanies. We are pioneering development of DHQs for treatment and prevention of hepatitisA. We have shown DHQs are highly active against HAV in cell culture and in mice. DHQs inhibitthe nucleotidyltransferases TENT4A/B, also called PAPD7/5, which play a role in cellular mRNA"quality control" and noncoding transcript metabolism and are necessary for efficient HBV andHAV RNA functions. However, their mechanism of action against HBV and HAV are distinct: whileDHQs promote degradation of HBV mRNAs, they do not affect HAV RNA stability. Instead DHQssuppress HAV RNA synthesis. The selective sensitivity of viral over host transcripts to DHQsoffered a new strategy of antiviral therapy with low risk for resistance. However, DHQdevelopment has been slowed and even suspended because of neurotoxicity concerns in long-term animal studies. We therefore produced a family of hepatoselective HS-DHQs that usereceptors enriched on hepatocytes to achieve a liver-selective distribution. Our lead HS-DHQs 2and 3 have been shown to have nano-molar activities against HAV in cell culture and they targethepatocytes in culture and are enriched in the liver in mice. We have now synthesized a family ofHS-DHQs to optimize their PK profiles. Our mouse studies suggest effective therapy for hepatitisA will require only brief antiviral therapy, and we propose that our HS-DHQs with less plasma andother tissue exposure will carry a low risk of neurotoxicity when used in this context. In this STTRPhase I application, we will perform lead optimization to advance HS-DHQs based not only onanti-HAV efficacy in tissue culture and PK study results, but also a neurotoxicity screen using anin vitro assay with primary rat neurons and in vivo distribution to neuronal tissues. The best HS-DHQs will be further studied for their efficacy in treating and preventing HAV infection in mice.HS-DHQs with the best antiviral, PK, and PD performance in murine models of HAV will then beadvanced through preclinical studies in Phase II necessary to support a human clinical study.

Public Health Relevance Statement:
Project Narrative There is no effective antiviral drug to treat acute hepatitis A. Despite an effective vaccine, hepatitis A virus (HAV) still causes thousands of hospitalizations and many deaths each year in the United States alone. It is a much more serious problem in the developing countries, and it is also an agent of bioterror concern. However, there is currently no effective antivirals to treat severe HAV infections. A drug called DHQ was under development for hepatitis B and also has activity against HAV but had neurotoxicity in culture and long-term animal studies. Harlingene Life Sciences has modified this drug to be hepatoselective (HS) and is developing it for HAV. HS-DHQ would be the first and only HAV antiviral drug to mitigate liver injury in acute hepatitis A.

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