Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure-activity studies.
The structure-based design, chemical synthesis, and biological evaluation of various peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (kobs/[I]) ranging from 60 to 280 000 M-1 s-1 and antiviral EC50's which approach 0.15 microM. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (kobs/[I] = 800 000 M-1 s-1) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 microM). A 1.9 A crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-2 3CP is also detailed.
Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA.
P S
PS
Dragovich
S E
SE
Webber
R E
RE
Babine
S A
SA
Fuhrman
A K
AK
Patick
D A
DA
Matthews
S H
SH
Reich
J T
JT
Marakovits
T J
TJ
Prins
R
R
Zhou
J
J
Tikhe
E S
ES
Littlefield
T M
TM
Bleckman
M B
MB
Wallace
T L
TL
Little
C E
CE
Ford
J W
JW
Meador
R A
RA
Ferre
E L
EL
Brown
S L
SL
Binford
D M
DM
DeLisle
S T
ST
Worland
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002461:Cell Line, Transformed; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012229:Rhinovirus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D014764:Viral Proteins
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases