Development of Small Molecule Therapeutics for Emerging Viral Agents

Ebolavirus species including Zaire (EBOV), Sudan (SUDV) and Bundibugyo (BDBV) are responsible for severe hemorrhagic fever outbreaks with high case fatalities in Africa. Weaponized pathogens present an additional threat to the health protection of the warfighter and first-generation prophylactic and therapeutic medical countermeasures (MCMs) may prove inadequate in biodefense settings. Ebolaviruses present both potential public health and bioweapons threats and the development of second-generation therapeutics targeting novel mechanisms for antiviral activity may help to provide auxiliary means of protection. We utilized a vesicular stomatitis virus (VSV) based pseudotyped virus platform to identify novel chemical series of Ebola virus cell entry inhibitors and through SAR expansion have identified compounds with submicromolar broad-spectrum ebolavirus antiviral activity. Lead compounds exhibit favorable in vitro and in vivo drug-like properties promoting them as attractive next generation Ebola inhibitors for the development of dual use therapeutics.