title: Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants.
abstract: HIV-1 integrase (IN) is the molecular target of the newly approved anti-AIDS drug raltegravir (MK-0518, Isentress) while elvitegravir (GS-9137, JTK-303) is in clinical trials. The aims of the present study were (1) to investigate and compare the effects of raltegravir and elvitegravir on the three IN-mediated reactions, 3'-processing (3'-P), strand transfer (ST), and disintegration, (2) to determine the biochemical activities of seven IN mutants (T66I, L74M, E92Q, F121Y, Q148K, S153Y, and N155H) previously selected from drug-resistant patients and isolates, and (3) to determine the resistance profile for raltegravir and elvitegravir in those IN mutants. Our findings demonstrate that both raltegravir and elvitegravir are potent IN inhibitors and are highly selective for the ST reaction of IN. Elvitegravir was more potent than raltegravir, but neither drug could block disintegration. All resistance mutations were at least partially impaired for ST. Q148K was also markedly impaired for 3'-P. Both drugs exhibited a parallel resistance profile, although resistance was generally greater for elvitegravir. Q148K and T66I conferred the highest resistance to both drugs while S153Y conferred relatively greater resistance to elvitegravir than raltegravir. Drug resistance could not be overcome by preincubating the drugs with IN, consistent with the binding of raltegravir and elvitegravir at the IN-DNA interface. Finally, we found an inverse correlation between resistance and catalytic activity of the IN mutants.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Marinello
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.forename: Anjali
authors.initials: A
authors.lastname: Bain
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D019943:Amino Acid Substitution; D002384:Catalysis; D004279:DNA, Viral / Q000737:chemistry* / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D020125:Mutation, Missense; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D000068898:Raltegravir Potassium; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019427:HIV Integrase