Optimizing Ridaifen-B analogs as potential therapeutics for Ebola viruses

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Summary Ebola virus disease (EVD) is caused by an infection with a group of viruses within the genus Ebolavirus. There are at least five species of Ebolavirus, Ebola virus (Zaire, EBOV), Ebola Sudan (SUDV), Bundibugyo virus (BDBV), Reston virus and Tai Forest virus (TAFV). Infections with these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates, and are associated with up to 90% mortality rates with EBOV. Because of the safety concerns, these viruses are designated as the biosafety level 4 agents. Currently there is no effective therapeutic treatments against Ebola virus infection and pathogenesis in humans. Thus the goal of this application is to develop GP-specific small molecule inhibitors as drugs which can be used prophylactically and therapeutically against EBOV and other Ebola virus infections. To achieve this, we screened an in-house library of small molecules, and identified numerous potent entry inhibitors against EBOV. We have identified a series of potent compounds and will use them as leads which will be chemically optimized and developed as an anti-Ebola virus therapy candidate. In this application, two specific aims are proposed: (1) structure- based optimization of the lead compounds, and (2) In vivo evaluation of the lead compounds against EBOV infection using animal models.