Discovery of novel cyclic peptide inhibitors of dengue virus NS2B-NS3 protease with antiviral activity
| Autor: | Akihiko Sato, Kouhei Matsui, Yoshito Numata, Haruka Maeda, Youhei Takagi, Yasuko Orba, Yutaka Yoshida, Kazunari Hattori, Hirofumi Sawa, Takeshi Kurosu, Haruaki Nobori, Kenichi Higashino |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
viruses medicine.medical_treatment Clinical Biochemistry Pharmaceutical Science Dengue virus medicine.disease_cause Antiviral Agents Peptides Cyclic 01 natural sciences Biochemistry Dengue 03 medical and health sciences Drug Discovery medicine Humans Peptide bond Protease Inhibitors Molecular Biology Peptide sequence chemistry.chemical_classification NS3 Protease Serine Endopeptidases Organic Chemistry virus diseases Dengue Virus biochemical phenomena metabolism and nutrition Cyclic peptide 0104 chemical sciences Molecular Docking Simulation NS2-3 protease 010404 medicinal & biomolecular chemistry 030104 developmental biology Enzyme chemistry Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:3586-3590 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2017.05.027 |
| Popis: | NS2B-NS3 protease is an essential enzyme for the replication of dengue virus (DENV), which continues to be a serious threat to worldwide public health. We designed and synthesized a series of cyclic peptides mimicking the substrates of this enzyme, and assayed their activity against the DENV-2 NS2B-NS3 protease. The introduction of aromatic residues at the appropriate positions and conformational restriction generated the most promising cyclic peptide with an IC50 of 0.95μM against NS2B-NS3 protease. Cyclic peptides with proper positioning of additional arginines and aromatic residues exhibited antiviral activity against DENV. Furthermore, replacing the C-terminal amide bond of the polybasic amino acid sequence with an amino methylene moiety stabilized the cyclic peptides against hydrolysis by NS2B-NS3 protease, while maintaining their enzyme inhibitory activity and antiviral activity. |
| Databáze: | OpenAIRE |
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