2. Academic Validation
  3. Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability

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

  • Antimicrob Agents Chemother. 2024 Apr 3;68(4):e0137323. doi: 10.1128/aac.01373-23.
Andrew Mulato 1,  Eric Lansdon 2,  Ron Aoyama 3,  Johannes Voigt 2,  Michael Lee 4,  Albert Liclican 4,  Gary Lee 4,  Eric Singer 1,  Brian Stafford 3,  Ruoyu Gong 4,  Bernard Murray 3,  Julie Chan 4,  Johnny Lee 4,  Yili Xu 4,  Shekeba Ahmadyar 4,  Ana Gonzalez 5,  Aesop Cho 5,  George J Stepan 4,  Uli Schmitz 2,  Brian Schultz 4,  Bruno Marchand 4,  Boris Brumshtein 4,  Ruth Wang 4,  Helen Yu 4,  Tomas Cihlar 1,  Lianhong Xu 5,  Stephen R Yant 1
Affiliations

Affiliations

  • 1 Department of Virology, Gilead Sciences, Foster City, California, USA.
  • 2 Department of Structural Biology and Chemistry, Gilead Sciences, Foster City, California, USA.
  • 3 Department of Drug Metabolism, Gilead Sciences, Foster City, California, USA.
  • 4 Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA.
  • 5 Department of Medicinal Chemistry, Gilead Sciences, Foster City, California, USA.
PMID: 38380945 DOI: 10.1128/aac.01373-23
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 resistant to drugs from other Antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.

Keywords

HIV; antiretroviral resistance; antiviral agents; antiviral pharmacology; drug discovery; pharmacokinetics; preclinical drug studies; protease.

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