Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics.
The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The ketomethylene-containing inhibitors typically display slightly reduced 3CP inhibition activity relative to the corresponding peptide-derived molecules, but they also exhibit significantly improved antiviral properties. Optimization of the ketomethylene-containing compounds is shown to provide several highly active 3C protease inhibitors which function as potent antirhinoviral agents (EC90 = <1 microM) against multiple virus serotypes in cell culture.
Dragovich
P S
PS
Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, California 92121, USA.
Prins
T J
TJ
Zhou
R
R
Fuhrman
S A
SA
Patick
A K
AK
Matthews
D A
DA
Ford
C E
CE
Meador
J W
JW
Ferre
R A
RA
Worland
S T
ST
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D012229:Rhinovirus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007659:Ketones; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases