Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors

Michael B. Plewe; Nadezda V. Sokolova; Vidyasagar Reddy Gantla; Eric R. 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

doi:10.1021/acsmedchemlett.0c00025

Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors

Michael B. Plewe, Nadezda V. Sokolova, Vidyasagar Reddy Gantla, Eric R. 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

Pathology

Research output: Contribution to journal › Article

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.

Original language	English (US)
Journal	ACS Medicinal Chemistry Letters
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00025
State	Accepted/In press - Jan 1 2020

Keywords

adamantane carboxamide
cell entry
Ebola virus
glycoprotein

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.0c00025

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Plewe, M. B., Sokolova, N. V., Gantla, V. R., Brown, E. R., Naik, S., Fetsko, A., Lorimer, D. D., Dranow, D. M., Smutney, H., Bullen, J., Sidhu, R., Master, A., Wang, J., Kallel, E. A., Zhang, L., Kalveram, B., Freiberg, A. N., Henkel, G., & McCormack, K. (Accepted/In press). Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors. ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.0c00025

Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors. / Plewe, Michael B.; Sokolova, Nadezda V.; Gantla, Vidyasagar Reddy; Brown, Eric R.; Naik, Shibani; Fetsko, Alexandra; Lorimer, Donald D.; Dranow, David M.; Smutney, Hayden; Bullen, Jameson; Sidhu, Rana; Master, Arshil; Wang, Junru; Kallel, E. Adam; Zhang, Lihong; Kalveram, Birte; Freiberg, Alexander N.; Henkel, Greg; McCormack, Ken.

In: ACS Medicinal Chemistry Letters, 01.01.2020.

Research output: Contribution to journal › Article

Plewe, MB, Sokolova, NV, Gantla, VR, Brown, ER, Naik, S, Fetsko, A, Lorimer, DD, Dranow, DM, Smutney, H, Bullen, J, Sidhu, R, Master, A, Wang, J, Kallel, EA, Zhang, L, Kalveram, B, Freiberg, AN, Henkel, G & McCormack, K 2020, 'Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors', ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.0c00025

Plewe, Michael B. ; Sokolova, Nadezda V. ; Gantla, Vidyasagar Reddy ; Brown, Eric R. ; Naik, Shibani ; Fetsko, Alexandra ; Lorimer, Donald D. ; Dranow, David M. ; Smutney, Hayden ; Bullen, Jameson ; Sidhu, Rana ; Master, Arshil ; Wang, Junru ; Kallel, E. Adam ; Zhang, Lihong ; Kalveram, Birte ; Freiberg, Alexander N. ; Henkel, Greg ; McCormack, Ken. / Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors. In: ACS Medicinal Chemistry Letters. 2020.

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