Hepato-selective dihydroquinolizinones active against hepatitis A virus in vitro and in vivo

  • Antiviral Res. 2025 May:237:106145. doi: 10.1016/j.antiviral.2025.106145.
Ichiro Misumi  1 ,  Zhizhou Yue  2 ,  Zhengyuan Jiang  3 ,  Anilkumar Karampoori  2 ,  Jason K Whitmire  4 ,  John M Cullen  5 ,  Timothy Block  2 ,  Stanley M Lemon  6 ,  Yanming Du  7 ,  You Li  8
Affiliations
  • 1. Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7292, USA.
  • 2. Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA; Harlingene Life Sciences, 3805 Old Easton Road, Doylestown, PA, 18902, USA.
  • 3. Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA.
  • 4. Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7292, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 5. College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27607, USA.
  • 6. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7292, USA; Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7292, USA.
  • 7. Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA; Harlingene Life Sciences, 3805 Old Easton Road, Doylestown, PA, 18902, USA. Electronic address: [email protected].
  • 8. Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: [email protected].
PMID: 40118118 DOI: 10.1016/j.antiviral.2025.106145
Abstract

Despite the considerable clinical and economic burden imposed by hepatitis A virus (HAV) Infection, both globally and in U.S., there are currently no available Antiviral therapies for the treatment of type A hepatitis. Here we describe novel third-generation hepato-selective dihydroquinolizinones (HS-DHQs) with cellular uptake mediated by transport via hepatocyte-specific solute organic anion transporter family members 1B1 and 1B3 (OATP1B1-B3). The lead HS-DHQ compound, HS83128, demonstrates robust inhibition of the host cell TENT4A/B terminal nucleotidyltransferases required for efficient HAV RNA synthesis (IC50 6-25nM), and potent Antiviral activity against HAV in Cell Culture (EC50 0.6 nM). Pharmacokinetic studies in CD-1 mice receiving comparable oral doses of HS83128 and a first-generation dihydroquinolizinone, RG7834, revealed a 5-fold increase in intrahepatic drug concentration and more than 10-fold improvement in liver versus nervous system tissue selectivity. Twice-daily oral administration of HS83128 rapidly arrested viral replication in HAV-infected IFNAR1-/- mice, reducing fecal virus shedding and cytokine markers of hepatic inflammation and reversing virus-induced liver injury. The hepato-selective nature of HS83128 may reduce the risk of neurologic and reproductive track toxicities observed with long-term administration of Other dihydroquinolizinones, making it a candidate for the first Antiviral therapy of hepatitis A.

Keywords
Antiviral drug; Hepatovirus; OATP1 transporter; PAPD poly(A) polymerase; Pharmacokinetics; Prophylaxis; TENT4 terminal nucleotidyltransferase; Therapy.
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