Novel mechanism of inhibition of HIV-1 reverse transcriptase by a new non-nucleoside analog, KM-1.

The Journal of Biological Chemistry
Louise Z WangK A Johnson

Abstract

2-Naphthalenesulfonic acid (4-hydroxy-7-[[[[5-hydroxy-6-[(4 cinnamylphenyl)azo]-7-sulfo-2-naphthalenyl]amino]-carbonyl]amino]-3-[(4-cinnamylphenyl)]azo (KM-1)) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that was designed to bind at an unconventional site on human immunodeficiency virus type 1 reverse transcriptase (RT) (Skillman, A. G., Maurer, K. W., Roe, D. C., Stauber, M. J., Eargle, D., Ewing, T. J., Muscate, A., Davioud-Charvet, E., Medaglia, M. V., Fisher, R. J., Arnold, E., Gao, H. Q., Buckheit, R., Boyer, P. L., Hughes, S. H., Kuntz, I. D., and Kenyon, G. L. (2002) Bioorg. Chem. 30, 443-458). We have investigated the mechanism by which KM-1 inhibits wild-type human immunodeficiency virus type 1 RT by using pre-steady state kinetic methods to examine the effect of KM-1 on the parameters governing the single nucleotide incorporation catalyzed by RT. Analysis of the pre-steady-state burst phase of dATP incorporation showed that KM-1 decreased the amplitude of the reaction as previously shown for other NNRTIs, because of the slow equilibration of the inhibitor with RT. In the ternary enzyme-DNA-KM-1 complex (E-DNA-I), incorporation of the next nucleotide onto the primer is blocked. However, unlike con...Continue Reading

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Citations

Sep 30, 2010·The Journal of Biological Chemistry·Matthew M SchuckmannStefan G Sarafianos
Sep 8, 2012·The Journal of Biological Chemistry·Kamalendra SinghStefan G Sarafianos
Oct 18, 2007·Nucleic Acids Research·Jeremiah W Hanes, Kenneth A Johnson
Nov 23, 2013·Future Medicinal Chemistry·Angela CoronaStuart F J Le Grice
Jun 4, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jennifer LaGilda Tachedjian
Mar 1, 2008·Virus Research·Dirk Jochmans
Mar 29, 2008·Virus Research·Nicolas Sluis-Cremer, Gilda Tachedjian
Jul 28, 2007·Protein Science : a Publication of the Protein Society·Qing XiaNicolas Sluis-Cremer
Nov 13, 2015·Memórias do Instituto Oswaldo Cruz·Lucianna Helene SantosErnesto Raúl Caffarena

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