Raltegravir: molecular basis of its mechanism of action.
Integration of the HIV-1 viral DNA generated by reverse transcription of the RNA genome into the host cell chromosomes is a key step of viral replication, catalyzed by the viral integrase. In October 2007, the first integrase inhibitor, raltegravir, was approved for clinical use under the name of Isentress superset. The results of the various clinical trials that have evaluated raltegravir have been very encouraging with regard to the immunological and virological efficacy and tolerance. However, as observed for other anti-retrovirals, specific resistance mutations have been identified in patients failing to respond to treatment with raltegravir. Although knowledge of the integrase structural biology remains fragmentary, the structures and modeling data available might provide relevant clues on the origin of the emergence of these resistance mutations. In this review, we describe the mechanism of action of this drug and the main data relating to its use in vivo, together with recent structural data important to our understanding of the origin of viral resistance.
Mouscadet
Jean-Francois
JF
LBPA, CNRS UMR8113, Ecole Normale Superieure de Cachan, 61 avenue du President Wilson, 94235 Cachan Cedex, France. mouscadet@lbpa.ens-cachan.fr
Tchertanov
Luba
L
D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008956:Models, Chemical; D011760:Pyrrolidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D016662:Virus Integration / Q000187:drug effects*
D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium