Breathing new life into West Nile virus therapeutics; discovery and study of zafirlukast as an NS2B-NS3 protease inhibitor
| Autor: | Anastasia A. Martinez, Bianca A. Espinosa, Niroshika Keppetipola, Nicholas T. Salzameda, Rebecca N. Adamek, Brent A. Thomas, Jennifer Chau, Edwardo Gonzalez |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Indoles viruses medicine.medical_treatment Allosteric regulation Phenylcarbamates Microbial Sensitivity Tests Viral Nonstructural Proteins Antiviral Agents Tosyl Compounds 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Drug Discovery medicine Structure–activity relationship Protease Inhibitors Zafirlukast IC50 Pharmacology Serine protease NS3 Sulfonamides Protease biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Serine Endopeptidases virus diseases General Medicine Virology 030104 developmental biology Docking (molecular) 030220 oncology & carcinogenesis biology.protein West Nile virus RNA Helicases medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 157 |
| ISSN: | 1768-3254 |
| Popis: | The West Nile virus (WNV) has spread throughout the world causing neuroinvasive diseases with no treatments available. The viral NS2B-NS3 protease is essential for WNV survival and replication in host cells and is a promising drug target. Through an enzymatic screen of the National Institute of Health clinical compound library, we report the discovery of zafirlukast, an FDA approved treatment for asthma, as an inhibitor for the WNV NS2B-NS3 protease. Zafirlukast was determined to inhibit the protease through a mixed mode mechanism with an IC50 value of 32 μM. A structure activity relationship study of zafirlukast revealed the cyclopentyl carbamate and N-aryl sulfonamide as structural elements crucial for NS2B-NS3 protease inhibition. Replacing the cyclopentyl with a phenyl improved inhibition, resulting in an IC50 of 22 μM. Experimental and computational docking analysis support the inhibition model of zafirlukast and analogs binding at an allosteric site on the NS3 protein, thereby disrupting the NS2B cofactor from binding, resulting in protease inhibition. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect