Tripeptide Aldehyde Inhibitors of Human Rhinovirus 3C Protease: Design, Synthesis, Biological Evaluation, and Cocrystal Structure Solution of P1 Glutamine Isosteric Replacements
| Autor: | J W Meador rd, K. Okano, Rose Ann Ferre, Edward L. Brown, Y Xin, Stephanie Webber, Susan L. Binford, Stephen T. Worland, Shella A. Fuhrman, R. A. Love, David A. Matthews, Clifford E. Ford, Amy K. Patick, Thomas F. Hendrickson, T L Little, Reich Siegfried Heinz |
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| Rok vydání: | 1998 |
| Předmět: |
Models
Molecular Rhinovirus Molecular model Picornain 3C Protein Conformation medicine.drug_class Stereochemistry Isostere Glutamine Molecular Conformation Carboxamide Tripeptide Cysteine Proteinase Inhibitors Crystallography X-Ray Antiviral Agents Cocrystal Viral Proteins chemistry.chemical_compound Amide Drug Discovery Peptide synthesis medicine Humans Cell Line Transformed Binding Sites Chemistry 3C Viral Proteases Cysteine Endopeptidases Drug Design Molecular Medicine Oligopeptides HeLa Cells |
| Zdroj: | Journal of Medicinal Chemistry. 41:2786-2805 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 Kis ranging from 0.005 to 0.64 microM. 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. |
| Databáze: | OpenAIRE |
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