Structural and binding analysis of pyrimidinol carboxylic acid and N-hydroxy quinazolinedione HIV-1 RNase H inhibitors

Antimicrob Agents Chemother. 2011 Jun;55(6):2905-15. doi: 10.1128/AAC.01594-10. Epub 2011 Apr 4.

Abstract

HIV-1 RNase H breaks down the intermediate RNA-DNA hybrids during reverse transcription, requiring two divalent metal ions for activity. Pyrimidinol carboxylic acid and N-hydroxy quinazolinedione inhibitors were designed to coordinate the two metal ions in the active site of RNase H. High-resolution (1.4 Å to 2.1 Å) crystal structures were determined with the isolated RNase H domain and reverse transcriptase (RT), which permit accurate assessment of the metal and water environment at the active site. The geometry of the metal coordination suggests that the inhibitors mimic a substrate state prior to phosphodiester catalysis. Surface plasmon resonance studies confirm metal-dependent binding to RNase H and demonstrate that the inhibitors do not bind at the polymerase active site of RT. Additional evaluation of the RNase H site reveals an open protein surface with few additional interactions to optimize active-site inhibitors.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / pharmacology*
  • Crystallization
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Molecular Conformation
  • Molecular Sequence Data
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology*
  • Ribonuclease H / antagonists & inhibitors*
  • Ribonuclease H / chemistry
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Pyrimidines
  • Quinazolinones
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase
  • Ribonuclease H