Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type‑1 Capsid Inhibitor Using a Multistep Computational Workflow

Poor metabolic stability of the human
immunodeficiency virus type-1
(HIV-1) capsid (CA) inhibitor PF-74 is a major concern
in its development toward clinical use. To improve on the metabolic
stability, we employed a novel multistep computationally driven workflow,
which facilitated the rapid design of improved PF-74 analogs
in an efficient manner. Using this workflow, we designed three compounds
that interact specifically with the CA interprotomer pocket, inhibit
HIV-1 infection, and demonstrate enantiomeric preference. Moreover,
using this workflow, we were able to increase the metabolic stability
204-fold in comparison to PF-74 in only three analog
steps. These results demonstrate our ability to rapidly design CA
compounds using a novel computational workflow that has improved metabolic
stability over the parental compound. This workflow can be further
applied to the redesign of PF-74 and other promising
inhibitors with a stability shortfall.