Journal article

Novel RU486 (mifepristone) analogues with increased activity against Venezuelan Equine Encephalitis Virus but reduced progesterone receptor antagonistic activity

Aaron DeBono, David R Thomas, Lindsay Lundberg, Chelsea Pinkham, Ying Cao, J Dinny Graham, Christine L Clarke, Kylie M Wagstaff, Sharon Shechter, Kylene Kehn-Hall, David A Jans

SCIENTIFIC REPORTS | NATURE PUBLISHING GROUP | Published : 2019

Abstract

There are currently no therapeutics to treat infection with the alphavirus Venezuelan equine encephalitis virus (VEEV), which causes flu-like symptoms leading to neurological symptoms in up to 14% of cases. Large outbreaks of VEEV can result in 10,000 s of human cases and mass equine death. We previously showed that mifepristone (RU486) has anti-VEEV activity (EC50 = 20 μM) and only limited cytotoxicity (CC50 > 100 μM), but a limitation in its use is its abortifacient activity resulting from its ability to antagonize the progesterone receptor (PR). Here we generate a suite of new mifepristone analogues with enhanced antiviral properties, succeeding in achieving >11-fold improvement in anti-V..

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University of Melbourne Researchers

Grants

Awarded by Defense Threat Reduction Agency


Awarded by National Health and Medical Research Council


Funding Acknowledgements

This work was funded through a Defense Threat Reduction Agency grant, HDTRA1-15-1-0014, to KKH, DAJ, and KMW. DTRA does not have any role in the design of the study and collection, analysis, and interpretation of data and nor in writing the manuscript. DAJ is an National Health and Medical Research Council Senior Principal Research Fellow (APP1103050).