Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability

作者：Andrew Mulato, E.B. Lansdon, Ron Aoyama, Johannes Voigt, Michael Lee, Albert Liclican, Gary Lee, Eric A. Singer, Brian Stafford, Ruoyu Gong, Bernard P. Murray, Julie Chan, Johnny W. Lee, Yili Xu, Shekeba Ahmadyar, Ana María González Noya, Aesop Cho, George Stepan, Uli Schmitz, Brian E. Schultz, Bruno Marchand, Boris Brumshtein, Ruth Wang, Helen Yu, Tomáš Cihlář, Lianhong Xu, Stephen R. Yant · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2024 · DOI：10.1128/aac.01373-23 · 被引用次数：7 · 研究领域：HIV/AIDS drug development and treatment、HIV Research and Treatment、Biochemical and Molecular Research

ABSTRACT Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resist...