Group designations—Mice.

Ebola virus (EBOV) causes a severe and often fatal hemorrhagic fever in humans for which effective postexposure countermeasures are lacking. Herein, we describe the evaluation of an S-adenosylhomocysteine hydrolase inhibitor, MSD-914, using mouse and nonhuman primate (NHP) models of lethal EBOV. Mice were completely protected from severe disease and death at doses as low as 0.31 mg/kg/day administered orally. From the pharmacological data and a toxicokinetic study, a predicted protective dose was selected for rhesus macaques (RMs). Surprisingly, orally administered MSD-914 was unable to protect RMs at doses as high as 0.8 mg/kg/day despite providing similar exposure of the drug to the efficacious dose observed in the mouse model.

埃博拉病毒（Ebola virus, EBOV）可引发人类罹患严重且常为致死性的出血热，目前尚无有效的暴露后防治措施。本研究报道了S-腺苷同型半胱氨酸水解酶（S-adenosylhomocysteine hydrolase）抑制剂MSD-914在致死性埃博拉病毒感染的小鼠与非人灵长类（nonhuman primate, NHP）模型中的评估结果。经口给药剂量低至0.31 mg/kg/日时，小鼠即可完全免受重症疾病与死亡威胁。基于药理学数据与毒代动力学研究结果，我们为恒河猴（rhesus macaques, RMs）选定了预测的保护性给药剂量。令人意外的是，尽管该药物在恒河猴体内的暴露水平与小鼠模型中起效剂量下的暴露水平相当，但经口给药剂量高达0.8 mg/kg/日时，MSD-914仍无法对恒河猴起到保护作用。