Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection
Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection
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DOI：
10.1128/aac.01711-17
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发表时间：
2018-02-01
影响因子：
4.9
通讯作者：
Madrid, Peter B.
中科院分区：
文献类型：
--
作者：
Ekins, Sean;Lingerfelt, Mary A.;Madrid, Peter B.
盐酸替罗龙是一种小分子口服生物利用药，在美国以外的地方被用作抗病毒药物。根据抗埃博拉病毒(EBOV)筛选数据训练的机器学习模型之前发现替罗龙是一种有效的体外EBOV抑制剂，使其成为治疗埃博拉病毒病(EVD)的候选药物。在本研究中，一系列体外ADMET(吸收、分布、代谢、排泄、毒性)测试表明，该药物具有良好的溶解性，高的Caco-2通透性，不是P-糖蛋白底物，对人的5种细胞色素P450酶(3A4、2D6、2C19、2C9和1A2)没有抑制活性。Tilorone具有52%的人血浆蛋白结合率，具有良好的血浆稳定性和小鼠肝微球的半衰期为48min。在小鼠身上进行的剂量范围寻找研究表明，最大耐受单次剂量为100 mg/kg体重。在小鼠体内的药代动力学研究表明，在2和10 mg/kg剂量水平下，药物被迅速吸收，血浆中游离药物的最大浓度和浓度-时间曲线下的面积随剂量增加而增加，雄性和雌性的半衰期约为18小时，尽管暴露在雄性小鼠中的剂量类似于2.5倍。剂量为25 mg/kg和50 mg/kg的Tilorone能有效地保护90%的小鼠免受致命攻击--适应于每天一次的腹腔注射。连续给药8天。随后的一项研究表明，每天ip替罗龙30 mg/kg。从攻击后2或24小时开始并持续到感染后第7天是完全保护的，这表明有希望的治疗EVD的活性。
Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machine-learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2-and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dose-dependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was similar to 2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD.