Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors with improved virology profile against gag polymorphisms

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2689-2694. doi: 10.1016/j.bmcl.2017.04.042. Epub 2017 Apr 20.

Abstract

A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC50 values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.

Keywords: Betulin; Bevirimat; GSK8999; HIV-1; Maturation inhibitor.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HIV-1 / drug effects*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Polymorphism, Genetic / drug effects*
  • Polymorphism, Genetic / genetics
  • Structure-Activity Relationship
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*
  • gag Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
  • gag Gene Products, Human Immunodeficiency Virus / genetics

Substances

  • Amides
  • Anti-HIV Agents
  • Triterpenes
  • gag Gene Products, Human Immunodeficiency Virus
  • betulin