Synthesis and in vitro study of novel neuraminidase inhibitors against avian influenza virus
| Autor: | Paolo Pengo, Andrea Gallotta, Jarinrat Kongkamnerd, Calogero Terregino, Wanchai De-Eknamkul, L. Beneduce, Vladimir Frecer, Stanislav Miertus, Nutthapon Jongaroonngamsang, Adolfo Prandi, Giorgio Fassina, Pornchai Rojsitthisak, Giovanni Cattoli, Ilaria Capua, Luca Cappelletti, Thanyada Rungrotmongkol, Pierfausto Seneci, Adelaide Milani |
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| Přispěvatelé: | Kongkamnerd, J., Cappelletti, L., Prandi, A., Seneci, P., Rungrotmongkol, T., Jongaroonngamsang, N., Frecer, V., Milani, A., Cattoli, G., Terregino, C., Capua, I., Beneduce, L., Gallotta, A., Pengo, Paolo, Fassina, G., Miertus, S., De Eknamkul, W. |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Oseltamivir Clinical Biochemistry Neuraminidase Pharmaceutical Science Avian influenza Neuraminidase inhibitor Pharmacology medicine.disease_cause Antiviral Agents Biochemistry law.invention Birds Influenza A Virus H7N3 Subtype chemistry.chemical_compound law Drug Discovery medicine Animals Molecular Biology IC50 Neuraminidase inhibitors chemistry.chemical_classification Binding Sites biology Chemistry Organic Chemistry Rational design virus diseases Screening assay Virology Influenza A virus subtype H5N1 Enzyme Influenza A virus Influenza in Birds Recombinant DNA biology.protein Influenza A Virus H7N1 Subtype Molecular Medicine Isopropyl |
| Zdroj: | Bioorganic & Medicinal Chemistry. 20:2152-2157 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2012.01.026 |
| Popis: | Evidences of oseltamivir resistant influenza patients raised the need of novel neuraminidase inhibitors. In this study, five oseltamivir analogs PMC-31–PMC-36, synthesised according to the outcomes of a rational design analysis aimed to investigate the effects of substitution at the 5-amino and 4-amido groups of oseltamivir on its antiviral activity, were screened for their inhibition against neuraminidase N1 and N3. The enzymes used as models were from the avian influenza A H7N1 and H7N3 viruses. The neuraminidase inhibition assay was carried out by using recombinant species obtained from a baculovirus expression system and the fluorogenic substrate MUNANA. The assay was validated by using oseltamivir carboxylate as a reference inhibitor. Among the tested compounds, PMC-36 showed the highest inhibition on N1 with an IC50 of 14.6 ± 3.0 nM (oseltamivir 25 ± 4 nM), while PMC-35 showed a significant inhibitory effect on N3 with an IC50 of 0.1 ± 0.03 nM (oseltamivir 0.2 ± 0.02 nM). The analysis of the inhibitory properties of this panel of compounds allowed a preliminary assessment of a structure–activity relationship for the modification of the 4-amido and 5-amino groups of oseltamivir carboxylate. The substitution of the acetamido group in the oseltamivir structure with a 2-butenylamido moiety reduced the observed activity, while the introduction of a propenylamido group was well tolerated. Substitution of the free 5-amino group of oseltamivir carboxylate with an azide, decreased the activity against both N1 and N3. When these structural changes were both introduced, a dramatic reduction of activity was observed for both N1 and N3. The alkylation of the free 5-amino group in oseltamivir carboxylate introducing an isopropyl group seemed to increase the inhibitory effect for both N1 and N3 neuraminidases, displaying a more pronounced effect against N1. |
| Databáze: | OpenAIRE |
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