jm301294g_si_001.pdf (1.16 MB)
Rational Design of Potent Non-Nucleoside Inhibitors of HIV‑1 Reverse Transcriptase
journal contribution
posted on 2012-12-13, 00:00 authored by Pek Chong, Paul 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 PeatA 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.