Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements
| Autor: | Ru Zhou, Stephen E. Webber, Thomas J. Prins, Joseph T. Marakovits, Rose Ann Ferre, Edward L. Brown, Caroline A. Lee, James E. V. Harr, Peter S. Dragovich, Tove Tuntland, Benjamin J. Burke, Amy K. Patick, Clifford E. Ford, Shella A. Fuhrman, Paul A. Rejto, Thomas F. Hendrickson, Maha Kosa, Stephen T. Worland, James W. Meador, David A. Matthews |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular Proteases Picornain 3C Lactams Rhinovirus Peptidomimetic Stereochemistry Glutamine Phenylalanine Drug Evaluation Preclinical Cysteine Proteinase Inhibitors Crystallography X-Ray Chemical synthesis Antiviral Agents Cell Line chemistry.chemical_compound Structure-Activity Relationship Viral Proteins Drug Discovery Structure–activity relationship Humans biology Molecular Mimicry 3C Viral Proteases Valine Isoxazoles Pyrrolidinones Cysteine Endopeptidases chemistry Enzyme inhibitor Drug Design Lactam biology.protein Molecular Medicine Oligopeptides Cysteine |
| Zdroj: | Journal of medicinal chemistry. 42(7) |
| ISSN: | 0022-2623 |
| Popis: | The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or 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 P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent. |
| Databáze: | OpenAIRE |
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