Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids.
Tripeptide-derived molecules incorporating N-methyl amino acid residues and C-terminal Michael acceptor moieties were evaluated as irreversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). Such compounds displayed good 3CP inhibition activity (k(obs)/[I] up to 610,000 M(-1) s(-1)) and potent in vitro antiviral properties (EC50 approaching 0.03 microM) when tested against HRV serotype-14.
Dragovich
P S
PS
Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
Webber
S E
SE
Prins
T J
TJ
Zhou
R
R
Marakovits
J T
JT
Tikhe
J G
JG
Fuhrman
S A
SA
Patick
A K
AK
Matthews
D A
DA
Ford
C E
CE
Brown
E L
EL
Binford
S L
SL
Meador
J W
JW
Ferre
R A
RA
Worland
S T
ST
D000086042:3C Viral Proteases; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D012229:Rhinovirus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins
D010455:Peptides; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases