Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants

被引:118
作者
Marinello, Jessica [1 ]
Marchand, Christophe [1 ]
Mott, Bryan T. [2 ]
Bain, Anjali [2 ]
Thomas, Craig J. [2 ]
Pommier, Yves [1 ]
机构
[1] NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA
[2] NHGRI, NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA
关键词
D O I
10.1021/bi800791q
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 T661 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.
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收藏
页码:9345 / 9354
页数:10
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