Open AccessDiscovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors
Author(s) -
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
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00025
Subject(s) - ebola virus , adamantane , vesicular stomatitis virus , infectivity , ebolavirus , virology , chemistry , lead compound , glycoprotein , virus , vesicular stomatitis indiana virus , in vitro , biology , biochemistry , organic chemistry
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.