Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 3, Pages 724-733Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01249
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Funding
- Biostruct-X project - EU seventh Framework Programme (FP7) [283570]
- Wellcome Trust
- UK Medical Research Council [MR/N00065X/1]
- Wellcome Trust [090532/Z/09/Z]
- MRC [G0500365, G19/3, MR/N00065X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C512145/1, BEP17785] Funding Source: researchfish
- Medical Research Council [G1100525, G19/3, G0500365, MR/N00065X/1] Funding Source: researchfish
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Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compounds. The binding constants (K-d) determined by thermal shift assay correlate with the protein inhibitor interactions as well as with the antiviral activities determined by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors.
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