Viruses (Sep 2024)

Preclinical Profile of the HIV-1 Maturation Inhibitor VH3739937

  • Brian McAuliffe,
  • Paul Falk,
  • Jie Chen,
  • Yan Chen,
  • Sing-Yuen Sit,
  • Jacob Swidorski,
  • Richard A. Hartz,
  • Li Xu,
  • Brian Venables,
  • Ny Sin,
  • Nicholas A. Meanwell,
  • Alicia Regueiro-Ren,
  • David Wensel,
  • Umesh Hanumegowda,
  • Mark Krystal

DOI
https://doi.org/10.3390/v16101508
Journal volume & issue
Vol. 16, no. 10
p. 1508

Abstract

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The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory strains, clinical isolates, and recombinant viruses examined, with half-maximal effective concentration (EC50) values ≤ 5.0 nM. In multiple-cycle assays, viruses less susceptible to other MIs, including A364V, were inhibited at EC50 values ≤ 8.0 nM and maximal percent inhibition (MPI) values ≥ 92%. However, VH-937 was less potent against A364V in single-cycle assays (EC50, 32.0 nM; MPI, 57%) and A364V emerged in one of four resistance selection cultures. Other substitutions were selected by VH-937, although re-engineered viruses with these sequences were non-functional in multiple-cycle assays. Measured dissociation rates from wild-type and A364V-containing VLPs help explain resistance to the A364V mutation. Overall, the in vitro antiviral activity of VH-937 supports its continued development as a treatment for HIV-1.

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