Mutations M184V and Y115F in HIV-1 reverse transcriptase discriminate against "nucleotide-competing reverse transcriptase inhibitors".

The Journal of Biological Chemistry
Maryam EhteshamiMatthias Götte

Abstract

Indolopyridones are potent inhibitors of reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1). Although the structure of these compounds differs from established nucleoside analogue RT inhibitors (NRTIs), previous studies suggest that the prototype compound INDOPY-1 may bind in close proximity to the polymerase active site. NRTI-associated mutations that are clustered around the active site confer decreased, e.g. M184V and Y115F, or increased, e.g. K65R, susceptibility to INDOPY-1. Here we have studied the underlying biochemical mechanism. RT enzymes containing the isolated mutations M184V and Y115F cause 2-3-fold increases in IC(50) values, while the combination of the two mutations causes a >15-fold increase. K65R can partially counteract these effects. Binding studies revealed that the M184V change reduces the affinity to INDOPY-1, while Y115F facilitates binding of the natural nucleotide substrate and the combined effects enhance the ability of the enzyme to discriminate against the inhibitor. Studies with other strategic mutations at residues Phe-61 and Ala-62, as well as the use of chemically modified templates shed further light on the putative binding site of the inhibitor and ternary complex fo...Continue Reading

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Citations

Oct 9, 2012·The Journal of Biological Chemistry·Stuart F J Le Grice
Dec 19, 2013·Antiviral Research·Luis Menéndez-Arias, Mar Alvarez
Mar 4, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jan BalzariniEddy Arnold
Dec 25, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·N N GuimarãesK S Cunha
Nov 3, 2016·PloS One·Aroldo Vieira de Moraes FilhoLee Chen-Chen
Aug 22, 2014·Journal of Medicinal Chemistry·Cyrus M LacbayYoula S Tsantrizos
Oct 31, 2014·The Journal of Biological Chemistry·Jean A BernatchezMatthias Götte
Jan 29, 2021·Chemical Reviews·Maria E CilentoStefan G Sarafianos
Oct 12, 2019·Journal of Medicinal Chemistry·F Xavier RuizEddy Arnold
Aug 12, 2009·Biochimica Et Biophysica Acta·Matthias GötteStuart F J Le Grice

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