1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV-1 Vif Antagonists
Idrees MohammedProgram
for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La
Jolla, California 92037, United StatesIndrasena Reddy KummethaDepartment
of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive, MC 0762, La Jolla, California 92093 United StatesGatikrushna SinghProgram
for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La
Jolla, California 92037, United StatesН. П. ШароваDivision
of Infectious Diseases, Miller School of Medicine, University of Miami, Miami, Florida 33136, United StatesGianluigi LichinchiDepartment
of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive, MC 0762, La Jolla, California 92093 United StatesJason DangDepartment
of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive, MC 0762, La Jolla, California 92093 United StatesMario StevensonDivision
of Infectious Diseases, Miller School of Medicine, University of Miami, Miami, Florida 33136, United StatesTariq M. RanaDepartment
of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive, MC 0762, La Jolla, California 92093 United States
2016en
ABI
Abstract
RN-18 based viral infectivity factor (Vif), Vif antagonists reduce viral infectivity by rescuing APOBEC3G (A3G) expression and enhancing A3G-dependent Vif degradation. Replacement of amide functionality in RN-18 (IC50 = 6 μM) by isosteric heterocycles resulted in the discovery of a 1,2,3-trizole, 1d (IC50 = 1.2 μM). We identified several potent HIV-1 inhibitors from a 1d based library including 5ax (IC50 = 0.01 μM), 5bx (0.2 μM), 2ey (0.4 μM), 5ey (0.6 μM), and 6bx (0.2 μM).
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Cited by 20 references