Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2' side chains.
A series of monopyrrolinone-based HIV-1 protease inhibitors possessing rationally designed P2' side chains have been synthesized and evaluated for activity against wild-type HIV-1 protease. The most potent inhibitor displays subnanomolar potency in vitro for the wild-type HIV-1 protease. Additionally, the monopyrrolinone inhibitors retain potency in cellular assays against clinically significant mutant forms of the virus. X-ray structures of these inhibitors bound in the wild-type enzyme reveal important insights into the observed biological activity.
Smith
Amos B
AB
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA. smithhab@sas.upenn.edu
Charnley
Adam K
AK
Harada
Hironori
H
Beiger
Jason J
JJ
Cantin
Louis-David
LD
Kenesky
Craig S
CS
Hirschmann
Ralph
R
Munshi
Sanjeev
S
Olsen
David B
DB
Stahlhut
Mark W
MW
Schleif
William A
WA
Kuo
Lawrence C
LC
D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D011760:Pyrrolidinones; D016333:HIV Protease