Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors
| Autor: | Mark T. Heise, Thomas E. Morrison, Subramaniam Ananthan, Joseph A. Maddry, Sanjay Sarkar, Jessica L. Smith, Kevin J Rodzinak, Nicole N. Haese, Daniel N. Streblow, Nathaniel J. Moorman, Cassilyn E. Streblow, Ashish K. Pathak, Vibha Pathak, Aaron D Streblow, Lynn Rasmussen, Fahim Ahmad, Corinne E. Augelli-Szafran, S Kaleem Ahmed, Victor R. DeFilippis, Robert Bostwick, Craig N. Kreklywich, Mark J. Suto, Sixue Zhang, Robbie Allen, Alec J. Hirsch, Jaden T Cowan, Babu L. Tekwani, Kiley Bonin, Nichole A. Tower, Wes Sander, Valerie J Smith, Mousheng Wu, John M Gerdes, Clayton R. Morrison, Omar Moukha-Chafiq |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Oxidoreductases Acting on CH-CH Group Donors Cell Survival Dihydroorotate Dehydrogenase Virus Replication Antiviral Agents 01 natural sciences Article Virus Cell Line Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound In vivo Drug Discovery Benzene Derivatives medicine Animals Humans Benzamide Cytotoxicity 030304 developmental biology 0303 health sciences Binding Sites Chemistry virus diseases Virology 0104 chemical sciences Mice Inbred C57BL Molecular Docking Simulation Disease Models Animal 010404 medicinal & biomolecular chemistry Titer Mechanism of action Viral replication Microsomes Liver Dihydroorotate dehydrogenase Chikungunya Fever Molecular Medicine Female medicine.symptom Chikungunya virus Half-Life |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c02183 |
| Popis: | A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC(90) = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC(50) = 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC(90) = 270 nM and VTR of 4.5 log at 10 μM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway. |
| Databáze: | OpenAIRE |
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