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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-guided optimization of HIV integrase strand transfer inhibitors Xue Zhi Zhao , Steven J Smith , Daniel P. Maskell , Mathieu Métifiot , Valerie E. Pye , Katherine Fesen , Christophe Marchand , Yves Pommier , Peter Cherepanov , Stephen H Hughes , Terrence R Burke Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b00596 Diamond Proposal Number(s): [9424, 13775] Open Access Show Abstract ▼ Abstract: Integrase mutations can reduce effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG) has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogs of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogs we have previously described.	Jul 2017

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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography

Structure-guided optimization of HIV integrase strand transfer inhibitors