2. Academic Validation
  3. Hepato-selective dihydroquinolizinones active against hepatitis A virus in vitro and in vivo

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

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: yanming.du@bblumberg.org.
  • 8 Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: you_li@med.unc.edu.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117650A
    99.85%, HBV Inhibitor
    HBV