Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease.
A two-fold (C2) symmetric inhibitor of the protease of human immunodeficiency virus type-1 (HIV-1) has been designed on the basis of the three-dimensional symmetry of the enzyme active site. The symmetric molecule inhibited both protease activity and acute HIV-1 infection in vitro, was at least 10,000-fold more potent against HIV-1 protease than against related enzymes, and appeared to be stable to degradative enzymes. The 2.8 angstrom crystal structure of the inhibitor-enzyme complex demonstrated that the inhibitor binds to the enzyme in a highly symmetric fashion.
Department of Computer-Assisted Molecular Design, Abbott Laboratories, Abbott Park, IL 60064.
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J
Erickson
D J
DJ
Neidhart
J
J
VanDrie
D J
DJ
Kempf
X C
XC
Wang
D W
DW
Norbeck
J J
JJ
Plattner
J W
JW
Rittenhouse
M
M
Turon
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N
Wideburg
D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D015684:Gene Products, pol / Q000378:metabolism*; D016333:HIV Protease; D015497:HIV-1 / Q000201:enzymology*; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology*; D011487:Protein Conformation; D013402:Sugar Alcohols / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D015684:Gene Products, pol; D011480:Protease Inhibitors; D013402:Sugar Alcohols; C065300:A 74704; D010450:Endopeptidases; D016333:HIV Protease; D014633:Valine