Structural Basis of HIV-1 Inhibition by Nucleotide-Competing Reverse Transcriptase Inhibitor INDOPY-1

J Med Chem. 2019 Nov 14;62(21):9996-10002. doi: 10.1021/acs.jmedchem.9b01289. Epub 2019 Oct 25.

Abstract

HIV-1 reverse transcriptase (RT) is an essential enzyme, targeting half of approved anti-AIDS drugs. While nucleoside RT inhibitors (NRTIs) are DNA chain terminators, the nucleotide-competing RT inhibitor (NcRTI) INDOPY-1 blocks dNTP binding to RT. Lack of structural information hindered INDOPY-1 improvement. Here we report the HIV-1 RT/DNA/INDOPY-1 crystal structure, revealing a unique mode of inhibitor binding at the polymerase active site without involving catalytic metal ions. The structure may enable new strategies for developing NcRTIs.

Publication types

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

MeSH terms

  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Models, Molecular
  • Nitriles / chemistry*
  • Nitriles / pharmacology*
  • Protein Conformation
  • Pyridones / chemistry*
  • Pyridones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*

Substances

  • 5-methyl-1-(4-nitrophenyl)-2-oxo-2,5-dihydro-1H-pyrido(3,2-b)indole-3-carbonitrile
  • Indoles
  • Nitriles
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase