TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.
TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.
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TPT 磺酸盐，一种单剂量口服杀血吸虫前药：体内功效、处置和代谢分析。
DOI：
10.1016/j.ijpddr.2018.10.004
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Caffrey,ConorR
中科院分区：
文献类型：
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作者：
Wolfe,AlanR;Neitz,RJeffrey;Burlingame,Mark;Suzuki,BrianM;Lim,KC;Scheideler,Mark;Nelson,DavidL;Benet,LeslieZ;Caffrey,ConorR
血吸虫病的治疗仅依赖一种药物：吡喹酮 (PZQ)。在寻找替代品的过程中，从之前的研究项目中获得了 15S-[2-(烷基氨基)烷]硫代硫酸，并在小鼠中进行了分析，以评估筛选剂量为 100mg/kg POQDx4 的曼氏血吸虫对成熟（>42 日龄）和幼年（21 日龄）曼氏血吸虫的功效。一种化合物，S-[2-(叔丁基氨基)-1-苯基乙烷]硫代硫酸（TPT磺酸盐）是最有效的，可分别减少雌性和雄性蠕虫负担≥90%和≥46%（成熟）以及≥89%和≥79%（幼虫）。相比之下，PZQ 使成熟雌性和雄性蠕虫的负担分别降低了 95% 和 94%，但对幼虫阶段无效。对于 7 日龄肺期蠕虫，TPT 磺酸盐仅在两倍剂量下才有效，雌性和雄性负担分别减少 95% 和 80%。在不同发育时间点（1、7、15、21和/或42日龄）单次口服剂量400和/或600mg/kg与QDx4数据一致；一旦寄生虫完成肺迁移，功效最强，女性和男性负担分别减少至少 90% 和 80%。在体外，TPT 磺酸盐对寄生虫没有活性，表明其具有前药作用机制。在小鼠体内，TPT 磺酸盐被完全吸收，并经历快速、非 CYP 介导的首过代谢，该代谢由脱硫启动并产生一系列代谢物。化学合成了最初形成的游离硫醇代谢物，称为TP硫醇；它呈剂量依赖性下降。曼氏吸虫和埃及血吸虫体外运动力。此外，当单次 50mg/kg IP 剂量给药时，33 日龄时 TP 硫醇降低。男性和女性的负担分别为35%和44%，器官肿大程度较轻。总体而言，TPT 磺酸盐的功效与 PZQ 具有竞争力。此外，杀寄生虫代谢物的表征有助于化学的理解和改进，以及作用机制和/或靶标的识别。
Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15 S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old)Schistosoma mansoniusing a screening dose of 100 mg/kg POQDx4. One compound,S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing female and male worm burdens by ≥ 90% and ≥46% (mature), and ≥89% and ≥79% (juvenile), respectively. In contrast, PZQ decreased mature female and male worm burdens by 95% and 94%, respectively, but was ineffective against juvenile stages. Against 7-day-old lung-stage worms, TPT sulfonate was only effective at twice the dose decreasing female and male burdens by 95 and 80%, respectively. Single oral doses at 400 and/or 600 mg/kg across various developmental time-points (1-, 7-, 15-, 21- and/or 42 day-old) were consistent with theQDx4 data; efficacy was strongest once the parasites had completed lung migration, and female and male burdens were decreased by at least 90% and 80%, respectively.In vitro,TPT sulfonate is inactive against the parasite suggesting a pro-drug mechanism of action. In mice, TPT sulfonate is fully absorbed and subject to rapid, non-CYP-mediated, first-pass metabolism that is initiated by desulfation and yields a series of metabolites. The initially-formed free thiol-containing metabolite, termed TP thiol, was chemically synthesized; it dose-dependently decreasedS. mansoniandSchistosoma haematobiummotilityin vitro. Also, when administered as a single 50 mg/kg IP dose, TP thiol decreased 33-day-oldS. mansonifemale and male burdens by 35% and 44%, with less severe organomegaly. Overall, TPT sulfonate's efficacy profile is competitive with that of PZQ. Also, the characterization of a parasiticidal metabolite facilitates an understanding and improvement of the chemistry, and identification of the mechanism of action and/or target.