Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 2. Peptide Structure−Activity Studies

• Published in: Journal of medicinal chemistry Vol. 41; no. 15; pp. 2819 - 2834
• Main Authors: Dragovich, Peter S, Webber, Stephen E, Babine, Robert E, Fuhrman, Shella A, Patick, Amy K, Matthews, David A, Reich, Siegfried H, Marakovits, Joseph T, Prins, Thomas J, Zhou, Ru, Tikhe, Jayashree, Littlefield, Ethel S, Bleckman, Ted M, Wallace, Michael B, Little, Thomas L, Ford, Clifford E, Meador, James W, Ferre, Rose Ann, Brown, Edward L, Binford, Susan L, DeLisle, Dorothy M, Worland, Stephen T
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 16-07-1998
• Subjects: 3C Viral Proteases; 3CP; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Binding Sites; Biological and medical sciences; Cell Line, Transformed; Crystallography, X-Ray; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - metabolism; Cysteine Proteinase Inhibitors - pharmacology; Drug Design; Drug Evaluation, Preclinical; Human rhinovirus; Humans; Medical sciences; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Rhinovirus - drug effects; Rhinovirus - enzymology; Structure-Activity Relationship; Viral Proteins; Peptides; Enzyme; Picornaviridae; Cysteine endopeptidases; Tripeptide; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Modeling; Human rhinovirus; Virus; Peptidases; Structure activity relation; Vinylic compound; Molecular model; Hydrolases; Antiviral; Carboxamide; Dicarboxylic acid; Picornain 3C; Chemical synthesis; Rhinovirus; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9800696

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 (k obs/[I]) ranging from 60 to 280 000 M-1 s-1 and antiviral EC50's which approach 0.15 μM. 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 (k obs/[I] = 800 000 M-1 s-1) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 μM). A 1.9 Å crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-2 3CP is also detailed.