Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors
Michael Plewe, Н.В. Соколова, Vidyasagar Reddy Gantla, Eric Brown, Shibani Naik, Alexandra Fetsko, Donald D. Lorimer, David M. Dranow, Hayden Smutney, Jameson Bullen, Rana Sidhu, Arshil Master, Junru Wang, E. Adam Kallel, Lihong Zhang, Birte Kalveram, Alexander N. Freiberg, Greg Henkel, Ken McCormack
Abstract
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 (EC50 values) of ∼10–15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC50 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.