Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses

J Biol Chem. 2000 Feb 25;275(8):5633-9. doi: 10.1074/jbc.275.8.5633.

Abstract

Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-1 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolylthiourea (PETT) series of non-nucleoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC(50) of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC(50) of 5 nM) and also inhibits HIV-2 RT (IC(50) of 2.2 microM). X-ray crystallographic structure determinations of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compounds bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer binding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT. PETT-2 was a noncompetitive inhibitor with respect to the dGTP substrate for both HIV-1 and HIV-2 RTs. PETT-2 was also a noncompetitive inhibitor with respect to a poly(rC).(dG) template primer for HIV-2 RT. These results are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecting the binding of PETT-2 compared with PETT-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Crystallography, X-Ray
  • DNA Primers / metabolism
  • Deoxyguanine Nucleotides / pharmacology
  • Dose-Response Relationship, Drug
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Inhibitory Concentration 50
  • Intercalating Agents / pharmacology*
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Protein Binding
  • Pyridines / chemistry*
  • Pyridines / pharmacology
  • RNA-Directed DNA Polymerase / metabolism*
  • Regression Analysis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Thiazoles / pharmacology*
  • Thiourea / analogs & derivatives*
  • Thiourea / chemistry
  • Thiourea / pharmacology
  • Triazoles / pharmacology*

Substances

  • DNA Primers
  • Deoxyguanine Nucleotides
  • Intercalating Agents
  • PETT 1
  • PETT 2
  • Pyridines
  • Reverse Transcriptase Inhibitors
  • Thiazoles
  • Triazoles
  • deoxyguanosine triphosphate
  • 2-phenyl-6-(2'-(4'-(ethoxycarbonyl)thiazolyl))thiazolo(3,2-b)(1,2,4)triazole
  • reverse transcriptase, Human immunodeficiency virus 2
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Thiourea

Associated data

  • PDB/1DTQ
  • PDB/1DTQSF
  • PDB/1DTT
  • PDB/1DTTSF