HIV-1 integrase strand transfer inhibitors that reduce susceptibility to drug resistant mutant integrases

Authors

• XZ Zhao
• H Peters
• SJ Smith
• DP Maskell
• M Metifiot
• VE Pye
• K Fesen
• C Marchand
• Y Pommier
• P Cherepanov
• SH Hughes
• TB Burke
• Jr

Abstract

HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs. There are currently three FDA-approved HIV-1 INSTIs: Merck’s Raltegravir (RAL) (October 2007); Gileads’ Elvitegravir (EVG) (August 2012) and GlaxoSmithKlines’ Dolutegravir (DTG) (August 2013). However, the emergence of drug-resistant IN mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. We developed non-cytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the highly homologous prototype foamy virus (PFV) integrase, that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3’-processing and the bound host DNA prior to strand transfer. Using this concept of “bi-substrate mimicry” we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA, but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.

Scientific Focus Area: Chemical Biology

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