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Science 17 February 1995:
Vol. 267. no. 5200, pp. 988 - 993
DOI: 10.1126/science.7532321
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Articles

Science, Vol 267, Issue 5200, 988-993
Copyright © 1995 by American Association for the Advancement of Science

articles

Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors

RA Spence, WM Kati, KS Anderson, and KA Johnson

Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park 16802.

The mechanism of inhibition of HIV-1 reverse transcriptase by three nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO each bind to a hydrophobic pocket in the enzyme-DNA complex close to the active site catalytic residues. Pre-steady-state kinetic analysis was used to establish the mechanism of inhibition by these noncompetitive inhibitors. Analysis of the pre-steady-state burst of DNA polymerization indicated that inhibitors blocked the chemical reaction, but did not interfere with nucleotide binding or the nucleotide-induced conformational change. Rather, in the presence of saturating concentrations of the inhibitors, the nucleoside triphosphate bound tightly (Kd, 100 nM), but nonproductively. The data suggest that an inhibitor combining the functionalities of a nonnucleoside inhibitor and a nucleotide analog could bind very tightly and specifically to reverse transcriptase and could be effective in the treatment of AIDS.


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Novel Mechanism of Inhibition of HIV-1 Reverse Transcriptase by a New Non-nucleoside Analog, KM-1.
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E. G. Argyris, J. M. Vanderkooi, P. S. Venkateswaran, B. K. Kay, and Y. Paterson (1999)
J. Biol. Chem. 274, 1549-1556
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Patterns of Resistance and Cross-Resistance to Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitors in Patients Treated with the Nonnucleoside Reverse Transcriptase Inhibitor Loviride.
V. Miller, M.-P. de Béthune, A. Kober, M. Stürmer, K. Hertogs, R. Pauwels, P. Stoffels, and S. Staszewski (1998)
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Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance.
H. Huang, R. Chopra, G. L. Verdine, and S. C. Harrison (1998)
Science 282, 1669-1675
   Abstract »    Full Text »
Hybrid Ty1/HIV-1 elements used to detect inhibitors and monitor the activity of HIV-1 reverse transcriptase.
D. V. Nissley, P. L. Boyer, D. J. Garfinkel, S. H. Hughes, and J. N. Strathern (1998)
PNAS 95, 13905-13910
   Abstract »    Full Text »    PDF »
Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor.
R. M. Esnouf, J. Ren, A. L. Hopkins, C. K. Ross, E. Y. Jones, D. K. Stammers, and D. I. Stuart (1997)
PNAS 94, 3984-3989
   Abstract »    Full Text »    PDF »
Poliovirus RNA-dependent RNA Polymerase (3Dpol). STRUCTURAL, BIOCHEMICAL, AND BIOLOGICAL ANALYSIS OF CONSERVED STRUCTURAL MOTIFS A AND B.
D. W. Gohara, S. Crotty, J. J. Arnold, J. D. Yoder, R. Andino, and C. E. Cameron (2000)
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   Abstract »    Full Text »    PDF »


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