resistance to integrase inhibitors抗整合酶抑制剂.pdfVIP

Viruses 2010, 2, 1347-1366; doi:10.3390/v2071347 OPEN ACCESS viruses ISSN 1999-4915 /journal/viruses Review Resistance to Integrase Inhibitors Mathieu Métifiot, Christophe Marchand, Kasthuraiah Maddali and Yves Pommier * Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA; E-Mails: metifiotma@ (M.M.); marchanc@ (C.M.); maddalik@ (K.M.) * Author to whom correspondence should be addressed; E-Mail: pommier@ ; Tel.: +1-301-496-5944; Fax: +1-301-402-0752. Received: 2 7 April 2010; in revised form: 17 June 2010 / Accepted: 19 June 2010 / Published: 25 June 2010 Abstract: Integrase (IN) is a clinically validated target for the treatment of human immunodeficiency virus infections and raltegravir exhibits remarkable clinical activity. The next most advanced IN inhibitor is elvitegravir. However, mutant viruses lead to treatment failure and mutations within the IN coding sequence appear to confer cross -resistance. The characterization of those mutations is critical for the development of second generation IN inhibitors to overcome resistance. This review focuses on IN resistance based on structural and biochemical data, and on the role of the IN flexible loop i.e., between residues G140-G149 in drug action and resistance. Keywords: AIDS; HIV-1 integrase; Raltegravir; Elvitegravir; GSK-1349572; GSK-1265744; interfacial inhibitors; resistance 1. Background During replic