Rational Design of Potent Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase
Journal of Medicinal Chemistry2012Vol. 55(23), pp. 10601–10609
Citations Over TimeTop 10% of 2012 papers
Pek Y. Chong, Paul R. Sebahar, Michael Youngman, Dulce Garrido, Huichang Zhang, Eugene L. Stewart, Robert T. Nolte, Liping Wang, Robert G. Ferris, Mark Edelstein, Kurt Weaver, Amanda Mathis, Andrew J. Peat
Abstract
A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.
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