Tripeptide Aldehyde Inhibitors of Human Rhinovirus 3C Protease:  Design, Synthesis, Biological Evaluation, and Cocrystal Structure Solution of P1 Glutamine Isosteric Replacements

• Published in: Journal of medicinal chemistry Vol. 41; no. 15; pp. 2786 - 2805
• Main Authors: Webber, Stephen E, Okano, Koji, Little, Thomas L, Reich, Siegfried H, Xin, Yue, Fuhrman, Shella A, Matthews, David A, Love, Robert A, Hendrickson, Thomas F, Patick, Amy K, Meador, James W, Ferre, Rose Ann, Brown, Edward L, Ford, Clifford E, Binford, Susan L, Worland, Stephen T
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 16-07-1998
• Subjects: 3C Viral Proteases; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; 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 - pharmacology; Drug Design; Glutamine - chemistry; HeLa Cells; Humans; Medical sciences; Models, Molecular; Molecular Conformation; Oligopeptides - chemical synthesis; Oligopeptides - metabolism; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Protein Conformation; Rhinovirus - drug effects; Rhinovirus - enzymology; Viral Proteins; Human; Peptides; Enzyme; Picornaviridae; Cysteine endopeptidases; Enzyme inhibitor; Inhibitor enzyme complex; Aldehyde; In vitro; Modeling; Human rhinovirus; Virus; Peptidases; Structure activity relation; Molecular model; Hydrolases; Antiviral; Peptide synthesis; Picornain 3C; Chemical synthesis; Rhinovirus; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980071x

The investigation of tripeptide aldehydes as reversible covalent inhibitors of human rhinovirus (HRV) 3C protease (3CP) is reported. Molecular models based on the apo crystal structure of HRV-14 3CP and other trypsin-like serine proteases were constructed to approximate the binding of peptide substrates, generate transition state models of P1−P1‘ amide cleavage, and propose novel tripeptide aldehydes. Glutaminal derivatives have limitations since they exist predominantly in the cyclic hemiaminal form. Therefore, several isosteric replacements for the P1 carboxamide side chain were designed and incorporated into the tripeptide aldehydes. These compounds were found to be potent inhibitors of purified HRV-14 3CP with K is ranging from 0.005 to 0.64 μM. Several have low micromolar antiviral activity when tested against HRV-14-infected H1-HeLa cells. The N-acetyl derivative 3 was also shown to be active against HRV serotypes 2, 16, and 89. High-resolution cocrystal structures of HRV-2 3CP, covalently bound to compounds 3, 15, and 16, were solved. These cocrystal structures were analyzed and compared with our original HRV-14 3CP−substrate and inhibitor models.