TY - JOUR
T1 - Crystallographic study of multi-drug resistant HIV-1 protease lopinavir complex
T2 - Mechanism of drug recognition and resistance
AU - Liu, Zhigang
AU - Yedidi, Ravikiran S.
AU - Wang, Yong
AU - Dewdney, Tamaria G.
AU - Reiter, Samuel J.
AU - Brunzelle, Joseph S.
AU - Kovari, Iulia A.
AU - Kovari, Ladislau C.
N1 - Funding Information:
This research was supported by the National Institutes of Health Grant AI65294 and the American Foundation for AIDS Research ( 106457-34-RGGN ).
PY - 2013/7/26
Y1 - 2013/7/26
N2 - Lopinavir (LPV) is a second generation HIV-1 protease inhibitor. Drug resistance has rapidly emerged against LPV since its US FDA approval on September 15, 2000. Mutations at residues 32I, L33F, 46I, 47A, I54V, V82A, I84V, and L90M render the protease drug resistant against LPV. We report the crystal structure of a clinical isolate multi-drug resistant (MDR) 769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90) complexed with LPV and the in vitro enzymatic IC50 of LPV against MDR 769. The structural and functional studies demonstrate significant drug resistance of MDR 769 against LPV, arising from reduced interactions between LPV and the protease target.
AB - Lopinavir (LPV) is a second generation HIV-1 protease inhibitor. Drug resistance has rapidly emerged against LPV since its US FDA approval on September 15, 2000. Mutations at residues 32I, L33F, 46I, 47A, I54V, V82A, I84V, and L90M render the protease drug resistant against LPV. We report the crystal structure of a clinical isolate multi-drug resistant (MDR) 769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90) complexed with LPV and the in vitro enzymatic IC50 of LPV against MDR 769. The structural and functional studies demonstrate significant drug resistance of MDR 769 against LPV, arising from reduced interactions between LPV and the protease target.
KW - HIV-1 protease
KW - IC50
KW - Lopinavir
KW - Multi-drug resistance
KW - X-ray crystallography
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U2 - 10.1016/j.bbrc.2013.06.027
DO - 10.1016/j.bbrc.2013.06.027
M3 - Article
C2 - 23792096
AN - SCOPUS:84880707937
SN - 0006-291X
VL - 437
SP - 199
EP - 204
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -
