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Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress.

Quinoxaline-based inhibitors of Ebola and Marburg VP40 egress.

Authors :
Loughran, H. Marie
Han, Ziying
Wrobel, Jay E.
Decker, Sarah E.
Ruthel, Gordon
Freedman, Bruce D.
Harty, Ronald N.
Reitz, Allen B.
Source :
Bioorganic & Medicinal Chemistry Letters. Aug2016, Vol. 26 Issue 15, p3429-3435. 7p.
Publication Year :
2016

Abstract

We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40–Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21 , 24 , 26 , 39 ), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
0960894X
Volume :
26
Issue :
15
Database :
Academic Search Index
Journal :
Bioorganic & Medicinal Chemistry Letters
Publication Type :
Academic Journal
Accession number :
116843605
Full Text :
https://doi.org/10.1016/j.bmcl.2016.06.053