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J Biol Chem, Vol. 275, Issue 8, 5633-5639, February 25, 2000

Phenylethylthiazolylthiourea (PETT) Non-nucleoside Inhibitors of HIV-1 and HIV-2 Reverse Transcriptases
STRUCTURAL AND BIOCHEMICAL ANALYSES^*

Jingshan Ren, Jonathan Diprose, Jonathan Warren, Robert M. Esnouf, Louise E. Bird, Shinji Ikemizu, Martin Slater^§, John Milton^§, Jan Balzarini^¶, David I. Stuart^**, and David K. Stammers^**

From the  Structural Biology Division, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom, the ^§ Glaxo Wellcome R and D, Medicines Research Centre, Stevenage, SG1 2NY, United Kingdom, the ^¶ Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium, and the  Oxford Centre for Molecular Sciences, New Chemistry Building, University of Oxford, South Parks Road, Oxford, OX1 3QT, United Kingdom

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 IC₅₀ of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC₅₀ of 5 nM) and also inhibits HIV-2 RT (IC₅₀ of 2.2 µM). 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.

The atomic coordinates and structure factors (codes 1dtq and 1dtqsf and 1dtt and 1dttsf) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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