Inhibition of HIV Maturation via Selective Unfolding and Cross-Linking of Gag Polyprotein by a Mercaptobenzamide Acetylator

J Am Chem Soc. 2019 May 22;141(20):8327-8338. doi: 10.1021/jacs.9b02743. Epub 2019 May 13.


For HIV to become infectious, any new virion produced from an infected cell must undergo a maturation process that involves the assembly of viral polyproteins Gag and Gag-Pol at the membrane surface. The self-assembly of these viral proteins drives formation of a new viral particle as well as the activation of HIV protease, which is needed to cleave the polyproteins so that the final core structure of the virus will properly form. Molecules that interfere with HIV maturation will prevent any new virions from infecting additional cells. In this manuscript, we characterize the unique mechanism by which a mercaptobenzamide thioester small molecule (SAMT-247) interferes with HIV maturation via a series of selective acetylations at highly conserved cysteine and lysine residues in Gag and Gag-Pol polyproteins. The results provide the first insights into how acetylation can be utilized to perturb the process of HIV maturation and reveal a new strategy to limit the infectivity of HIV.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Anti-HIV Agents / pharmacology*
  • Benzamides / pharmacology*
  • Cell Line
  • Cysteine / chemistry
  • Fusion Proteins, gag-pol / chemistry
  • Fusion Proteins, gag-pol / drug effects
  • HIV / drug effects*
  • Humans
  • Lysine / chemistry
  • Protein Unfolding / drug effects*
  • Virus Assembly / drug effects*
  • gag Gene Products, Human Immunodeficiency Virus / chemistry
  • gag Gene Products, Human Immunodeficiency Virus / drug effects*


  • Anti-HIV Agents
  • Benzamides
  • Fusion Proteins, gag-pol
  • gag Gene Products, Human Immunodeficiency Virus
  • Lysine
  • Cysteine