新型 RU486（米非司酮）类似物对委内瑞拉马脑炎病毒的活性增强，但孕激素受体拮抗活性降低。

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

机构信息

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.

Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology School of Biomedical Sciences, Monash University, Melbourne, Australia.

出版信息

Sci Rep. 2019 Feb 22;9(1):2634. doi: 10.1038/s41598-019-38671-y.

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 (EC = 20 μM) and only limited cytotoxicity (CC > 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-VEEV activity with no detectable increase in toxicity. Importantly, we were able to derive a lead compound with an EC of 7.2 µM 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.

目前尚无治疗甲型委内瑞拉马脑炎病毒（VEEV）感染的疗法，该病毒可引起类似流感的症状，在多达 14%的病例中导致神经系统症状。VEEV 的大规模爆发可导致数千例人类病例和大量马匹死亡。我们之前曾表明，米非司酮（RU486）具有抗 VEEV 活性（EC = 20 μM），且仅有有限的细胞毒性（CC > 100 μM），但其应用受限是因为其作为孕激素受体（PR）拮抗剂的抗早孕活性。在这里，我们生成了一系列具有增强抗病毒特性的新型米非司酮类似物，成功地将抗 VEEV 活性提高了 11 倍以上，而毒性却没有明显增加。重要的是，我们能够获得一种 EC 为 7.2 μM 的先导化合物，且没有检测到 PR 拮抗活性。最后，根据我们的 SAR 分析，我们提出了进一步开发这些类似物作为安全有效的抗 VEEV 药物的途径。