Background:
VH3739937 (VH937) is a next generation maturation inhibitor (MI) currently in clinical trials. We report here on its preclinical profile.
Methods:
Replication competent and single cycle inhibition assays were performed using a cohort of clinical isolates or site-directed mutant (SDM) viruses. Biochemical experiments using purified viral like particles (VLPs) were performed, while a radiolabeled surrogate compound was used to examine binding kinetics to viral-like particles (VLPs). Resistance selection was carried out using NL4-3 virus at escalating concentrations of VH937. DMPK studies were also carried out.
Results:
Biochemical experiments showed VH937 to be a bona fide MI. VH937 is a pan-genotypic MI that was active against all HIV-1 viruses examined. EC50s of 1-5 nM were obtained against 8 laboratory strains and 43 clinical isolates. VH937 was also highly potent against all SDM polymorphisms previously identified as causing reduced susceptibility to first generation MIs. VH937 was partially active against a replication competent A364V mutant, with an EC50 of 5 nM and a maximum percent inhibition (MPI) of 95%. However, A364V could be selected under escalating VH937 conditions in cell culture, potentially explained by its weaker activity in a single cycle inhibition assay (EC…50=32 nM; MPI=57%). Other mutations selected by VH937 included T332P, L363W or the triple mutant H144Y/V362I/R384K. However, whereas each of these mutations induced highly reduced susceptibility in a single cycle assay, incorporation of any of these mutations into a replicating virus clone did not produce functional virus. The surrogate compound bound to an NL…4-3 VLP with a binding affinity of 3.3 ± 0.8 nM and had a dissociative half-life of 4125 minutes (almost 3 days), showing the compound binds avidly and dissociates slowly. This was in agreement with SP1 cleavage data obtained with VLPs. Finally, VH937 was ~93.3% protein bound in 100% human serum and exhibited DMPK profiles suitable for clinical development.
Conclusions:
The pre-clinical virology profile of VH937 supported the progression of this MI into clinical development.