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Indolopyridones inhibit human immunodeficiency virus reverse transcriptase with a novel mechanism of action

All Rights Reserved. Indolopyridones inhibit human immunodeficiency virus reverse transcriptase with a novel mechanism of action. Jochmans, Dirk; Deval, Jerome; Kesteleyn, Bart; Van Marck, Herwig; Bettens, Eva; De Baere, Inky; Dehertogh, Pascale; Ivens, Tania; Van Ginderen, Marcia; Van Schoubroeck, Bertrand; Ehteshami, Maryam; Wigerinck, Piet; Gotte, Matthias; Hertogs, Kurt (Tibotec BVBA, Mechelen 2800, Belg.In this study，352548-47-1 is also used.). Journal of Virology, 80(24), 12283-12292 (English) 2006 American Society for Microbiology. CODEN: JOVIAM. ISSN: 0022-538X. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) We have discovered a novel class of human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors that block the polymn. reaction in a mode distinct from those of the nucleoside or nucleotide RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). For this class of indolopyridone compds., steady-state kinetics revealed competitive inhibition with respect to the nucleotide substrate. Despite substantial structural differences with classical chain terminators or natural nucleotides, these data suggest that the nucleotide binding site of HIV RT may accommodate this novel class of RT inhibitors. To test this hypothesis, we have studied the mechanism of action of the prototype compd. indolopyridone-1 (INDOPY-1) using a variety of complementary biochem. tools. Time course expts. with heteropolymeric templates showed "hot spots" for inhibition following the incorporation of pyrimidines (T>C). Moreover, binding studies and site-specific footprinting expts. revealed that INDOPY-1 traps the complex in the posttranslocational state, preventing binding and incorporation of the next complementary nucleotide. The novel mode of action translates into a unique resistance profile. While INDOPY-1 susceptibility is unaffected by mutations assocd. with NNRTI or multidrug NRTI resistance, mutations M184V and Y115F are assocd. with decreased susceptibility, and mutation K65R confers hypersusceptibility to INDOPY-1. This resistance profile provides addnl. evidence for active site binding. In conclusion, this class of indolopyridones can occupy the nucleotide binding site of HIV RT by forming a stable ternary complex whose stability is mainly dependent on the nature of the primer 3' end. .