ViiV Healthcare, 36 East Industrial Road, Branford, CT 06405, USA.
Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Viruses. 2024 Sep 24;16(10):1508. doi: 10.3390/v16101508.
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 (EC) values ≤ 5.0 nM. In multiple-cycle assays, viruses less susceptible to other MIs, including A364V, were inhibited at EC values ≤ 8.0 nM and maximal percent inhibition (MPI) values ≥ 92%. However, VH-937 was less potent against A364V in single-cycle assays (EC, 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.
HIV-1 成熟抑制剂（MI）VH3739937（VH-937）抑制衣壳与间隔肽 1 之间的切割，并且在人体中具有与每周一次给药相容的口服半衰期。在此，描述了 VH-937 的抗病毒特性。VH-937 对所有 HIV-1 实验室株、临床分离株和重组病毒均表现出强大的抗病毒活性，半数最大有效浓度（EC）值≤5.0 nM。在多轮测定中，对其他 MI （包括 A364V）敏感性较低的病毒，其 EC 值≤8.0 nM，最大百分比抑制（MPI）值≥92%。然而，VH-937 在单轮测定中对 A364V 的效力较低（EC 值为 32.0 nM；MPI 值为 57%），并且在四个耐药选择培养物中有一种出现了 A364V 。尽管具有这些序列的经过重新设计的病毒在多轮测定中没有功能，但 VH-937 选择了其他取代。从野生型和含有 A364V 的 VLPs 中测量的解离速率有助于解释对 A364V 突变的耐药性。总体而言，VH-937 的体外抗病毒活性支持其继续开发为 HIV-1 的治疗方法。
