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. 2024 Sep 24;16(10):1508.
doi: 10.3390/v16101508.

Preclinical Profile of the HIV-1 Maturation Inhibitor VH3739937

Brian McAuliffe  1 , Paul Falk  1 , Jie Chen  2 , Yan Chen  2 , Sing-Yuen Sit  2 , Jacob Swidorski  2 , Richard A Hartz  2 , Li Xu  2 , Brian Venables  2 , Ny Sin  2 , Nicholas A Meanwell  2 , Alicia Regueiro-Ren  2 , David Wensel  1 , Umesh Hanumegowda  1 , Mark Krystal  1
Affiliations

Preclinical Profile of the HIV-1 Maturation Inhibitor VH3739937

Brian McAuliffe et al. Viruses. .

Abstract

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.

Keywords: antiviral activity; dissociative half-life; diverse HIV-1 subtypes; resistance selection.

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Conflict of interest statement

B.M., P.F., D.W., U.H., and M.K. are employees of ViiV Healthcare and may own stock in GSK. J.C., Y.C., S.-Y.S., J.S., R.A.H., L.X., B.V., N.S., N.A.M., and A.R.-R. are employees of Bristol Myers Squibb. J.S. and B.V. are co-inventors on patent WO 2017/134596 Al. R.A.H. is co-inventor on patent 11,084,845 B2. The funder of this study had a role in the study design, data collection, data analysis, data interpretation, and writing of the report. All authors had full access to the data and are responsible for the accuracy and completeness of this report. The corresponding author had final responsibility for the decision to submit for publication.

Figures

Figure 1
Figure 1
Chemical structure of VH3739937. The C20/29 double bond (red) was tritiated to create 3[H]-BMT-266754, the radiolabeled surrogate for VH3739937.
Figure 2
Figure 2
Inhibition of p24 appearance in a virus-like particle cleavage assay. (A) Delipidated wild-type or (B) mutant virus-like particles were pre-incubated with VH3739937, GSK3640254, GSK3532795, bevirimat, or dimethyl sulfoxide and then mixed with HIV-1 protease. Aliquots removed at the indicated time points were digested overnight with trypsin and then analyzed by liquid chromatography with mass spectrometry. Percent inhibition was measured relative to the appearance of p24 in the dimethyl sulfoxide control. GSK’254, GSK3640254; GSK’795, GSK3532795; VH-937, VH3739937.
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