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; Donald D. Lorimer; David M. Dranow; David M. Dranow; Hayden Smutney; Hayden Smutney; Jameson Bullen; Jameson Bullen; Rana Sidhu; Rana Sidhu; Arshil Master; Arshil Master; Junru Wang; 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, Donald D. Lorimer, David M. Dranow, David M. Dranow, Hayden Smutney, Hayden Smutney, Jameson Bullen, Jameson Bullen, Rana Sidhu, Rana Sidhu, Arshil Master, Arshil Master, Junru Wang, Junru WangE. Adam Kallel, Lihong Zhang, Birte Kalveram, Alexander N. Freiberg, Greg Henkel, Ken McCormack

Pathology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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)
Pages (from-to)	1160-1167
Number of pages	8
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	6
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00025
State	Published - Jun 11 2020

Keywords

Ebola virus
adamantane carboxamide
cell entry
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., Lorimer, D. D., Dranow, D. M., Dranow, D. M., Smutney, H., Smutney, H., Bullen, J., Bullen, J., Sidhu, R., Sidhu, R., Master, A., Master, A., Wang, J., ... McCormack, K. (2020). Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors. ACS Medicinal Chemistry Letters, 11(6), 1160-1167. https://doi.org/10.1021/acsmedchemlett.0c00025

Plewe, MB, Sokolova, NV, Gantla, VR, Brown, ER, Naik, S, Fetsko, A, Lorimer, DD, Lorimer, DD, Dranow, DM, Dranow, DM, Smutney, H, Smutney, H, Bullen, J, Bullen, J, Sidhu, R, Sidhu, R, Master, A, Master, A, Wang, J, 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, vol. 11, no. 6, pp. 1160-1167. https://doi.org/10.1021/acsmedchemlett.0c00025

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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.",

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author = "Plewe, {Michael B.} and Sokolova, {Nadezda V.} and Gantla, {Vidyasagar Reddy} and Brown, {Eric R.} and Shibani Naik and Alexandra Fetsko and Lorimer, {Donald D.} and Lorimer, {Donald D.} and Dranow, {David M.} and Dranow, {David M.} and Hayden Smutney and Hayden Smutney and Jameson Bullen and Jameson Bullen and Rana Sidhu and Rana Sidhu and Arshil Master and Arshil Master and Junru Wang and Junru Wang and Kallel, {E. Adam} and Lihong Zhang and Birte Kalveram and Freiberg, {Alexander N.} and Greg Henkel and Ken McCormack",

note = "Funding Information: This work was funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under SIBR grants R43AI118207 and R43AI138878 and Contract #HHSN272201700059C. Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

year = "2020",

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doi = "10.1021/acsmedchemlett.0c00025",

language = "English (US)",

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AU - Gantla, Vidyasagar Reddy

AU - Brown, Eric R.

AU - Naik, Shibani

AU - Fetsko, Alexandra

AU - Lorimer, Donald D.

AU - Dranow, David M.

AU - Smutney, Hayden

AU - Bullen, Jameson

AU - Sidhu, Rana

AU - Master, Arshil

AU - Wang, Junru

AU - Kallel, E. Adam

AU - Zhang, Lihong

AU - Kalveram, Birte

AU - Freiberg, Alexander N.

AU - Henkel, Greg

AU - McCormack, Ken

N1 - Funding Information: This work was funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under SIBR grants R43AI118207 and R43AI138878 and Contract #HHSN272201700059C. Publisher Copyright: Copyright © 2020 American Chemical Society.

PY - 2020/6/11

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N2 - 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.

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

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Keywords

ASJC Scopus subject areas

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