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
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..View full abstract
Awarded by Defense Threat Reduction Agency
Awarded by National Health and Medical Research Council
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).