Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors
| Autor: | Eric Brown, E. Adam Kallel, Donald D. Lorimer, Arshil Master, Ken McCormack, Alexandra Fetsko, David M. Dranow, Nadezda V. Sokolova, Rana Sidhu, Alexander N. Freiberg, Vidyasagar Reddy Gantla, Plewe Michael Bruno, Jameson Bullen, Greg Henkel, Junru Wang, Shibani Naik, Birte Kalveram, Hayden Smutney, Lihong Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
Cell entry
chemistry.chemical_classification Ebola virus 010405 organic chemistry medicine.drug_class viruses Adamantane Organic Chemistry Carboxamide medicine.disease_cause 01 natural sciences Biochemistry Virology 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry Drug Discovery medicine Glycoprotein |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] We identified and explored the structure–activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC(50) values) of ∼10–15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC(50) activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates. |
| Databáze: | OpenAIRE |
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