4.7 Article

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

Journal

SCIENTIFIC REPORTS
Volume 9, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-38671-y

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Funding

  1. Defense Threat Reduction Agency [HDTRA1-15-1-0014]
  2. National Health and Medical Research Council [APP1103050]

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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 mu M) and only limited cytotoxicity (CC50 > 100 mu M), 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-VEEV activity with no detectable increase in toxicity. Importantly, we were able to derive a lead compound with an EC50 of 7.2 mu M and no detectable PR antagonism activity. Finally, based on our SAR analysis we propose avenues for the further development of these analogues as safe and effective anti-VEEV agents.

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