The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC 50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1′-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3−14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [Nature 2016, 531, 381−385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.

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Adsorption and gas-liquid chromatography separate toxaphene into at least 175 polychlorinated 10-carbon compounds including Cl(6), Cl(7), Cl(8), Cl(9), and Cl(10) derivatives. One toxic component is 2,2,5-endo,6-exo,8,9,10-heptachlorobornane. Rats metabolically dechlorinate toxaphene, removing about half of the chlorine from the technical insecticide and from each of seven subfractions of varying composition and toxicity.

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