Structure-based design and optimization of potent inhibitors of the adenoviral protease
| Autor: | Samu Melkko, N. Jarousse, David Archer Ellis, Finton Sirockin, A. Bernardi, Aengus Mac Sweeney, Paul Erbel, Paul Ramage, Philipp Grosche, Eva Altmann, Keith D. Combrink, Nicola Hughes |
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| Rok vydání: | 2015 |
| Předmět: |
Adenain
Drug Peptidomimetic medicine.medical_treatment media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Viral Conjunctivitis Crystallography X-Ray Antiviral Agents Biochemistry Adenoviridae Structure-Activity Relationship Viral Proteins Drug Discovery medicine Humans Effective treatment Protease Inhibitors Molecular Biology media_common Binding Sites Protease Tetrapeptide Chemistry Organic Chemistry Virology Protein Structure Tertiary Molecular Docking Simulation Cysteine Endopeptidases HEK293 Cells Drug Design Molecular Medicine Structure based Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:438-443 |
| ISSN: | 0960-894X |
| Popis: | Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds. |
| Databáze: | OpenAIRE |
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