The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase
| Autor: | Jeremy E. Wulff, Martin J. Boulanger, Tracy Chan, Michael G. Brant, Jeremy W. Mason, Martine D. Lunke, Caleb M. Bromba, Martin Petric |
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| Rok vydání: | 2011 |
| Předmět: |
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Molecular Drug medicine.drug_class media_common.quotation_subject Clinical Biochemistry Acids Carbocyclic Neuraminidase Pharmaceutical Science Cyclopentanes Pharmacology Crystallography X-Ray Antiviral Agents Guanidines Biochemistry Inhibitory Concentration 50 chemistry.chemical_compound Zanamivir Drug Discovery medicine Humans Potency Enzyme Inhibitors Guanidine Molecular Biology media_common Dose-Response Relationship Drug Molecular Structure biology Neuraminidase inhibitor Chemistry Organic Chemistry Virology Recombinant Proteins In vitro Influenza A virus Drug Design biology.protein Molecular Medicine Peramivir Protein Binding medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 21:7137-7141 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2011.09.076 |
| Popis: | The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function. |
| Databáze: | OpenAIRE |
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