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

Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.

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. Unique Identifier : AIDSLINE PDB/1DTTSF
Ren J; Diprose J; Warren J; Esnouf RM; Bird LE; Ikemizu S; Slater M; Milton J; Balzarini J; Stuart DI; Stammers DK; Structural Biology Division, The Wellcome Trust Centre for Human; Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN,; United Kingdom.

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.

Keywords: JOURNAL ARTICLE Binding, Competitive Crystallography, X-Ray Deoxyguanine Nucleotides/PHARMACOLOGY Dose-Response Relationship, Drug DNA Primers/METABOLISM HIV-1 Reverse Transcriptase/*ANTAGONISTS & INHIB Inhibitory Concentration 50 Intercalating Agents/*PHARMACOLOGY Kinetics Models, Chemical Models, Molecular Protein Binding Pyridines/*CHEMISTRY/PHARMACOLOGY Regression Analysis Reverse Transcriptase Inhibitors/CHEMISTRY/*PHARMACOLOGY RNA-Directed DNA Polymerase/*METABOLISM Support, Non-U.S. Gov't Thiazoles/*PHARMACOLOGY Thiourea/*ANALOGS & DERIVATIVES/CHEMISTRY/PHARMACOLOGY Triazoles/*PHARMACOLOGY

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