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HIV‐1 IN alternative molecular recognition of DNA induced by raltegravir resistance mutations
Author(s) -
Mouscadet JeanFrançois,
Arora Rohit,
André Joseph,
Lambry JeanChristophe,
Delelis Olivier,
Malet Isabelle,
Marcelin AnneGeneviève,
Calvez Vincent,
Tchertanov Luba
Publication year - 2009
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/jmr.970
Subject(s) - raltegravir , integrase , integrase inhibitor , mutant , dna , chemistry , integrases , computational biology , biology , biochemistry , genetics , human immunodeficiency virus (hiv) , virology , gene , antiretroviral therapy , viral load
Virologic failure during treatment with raltegravir, the first effective drug targeting HIV integrase, is associated with two exclusive pathways involving either Q148H/R/K, G140S/A or N155H mutations. We carried out a detailed analysis of the molecular and structural effects of these mutations. We observed no topological change in the integrase core domain, with conservation of a newly identified Ω‐shaped hairpin containing the Q148 residue, in particular. In contrast, the mutations greatly altered the specificity of DNA recognition by integrase. The native residues displayed a clear preference for adenine, whereas the mutant residues strongly favored pyrimidines. Raltegravir may bind to N155 and/or Q148 residues as an adenine bioisoster. This may account for the selected mutations impairing raltegravir binding while allowing alternative DNA recognition by integrase. This study opens up new opportunities for the design of integrase inhibitors active against raltegravir‐resistant viruses. Copyright © 2009 John Wiley & Sons, Ltd.