Structure-based design of ketone-containing, tripeptidyl human rhinovirus 3C protease inhibitors.
Tripeptide-derived molecules incorporating C-terminal ketone electrophiles were evaluated as reversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). An optimized example of such compounds displayed potent 3CP inhibition activity (K = 0.0045 microM) and in vitro antiviral properties (EC50=0.34 microM) when tested against HRV serotype-14.
Dragovich
P S
PS
Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. psd@agouron.com
Zhou
R
R
Webber
S E
SE
Prins
T J
TJ
Kwok
A K
AK
Okano
K
K
Fuhrman
S A
SA
Zalman
L S
LS
Maldonado
F C
FC
Brown
E L
EL
Meador
J W
JW
Patick
A K
AK
Ford
C E
CE
Brothers
M A
MA
Binford
S L
SL
Matthews
D A
DA
Ferre
R A
RA
Worland
S T
ST
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D012229:Rhinovirus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D009842:Oligopeptides; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases