Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria

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• 作者：Erica M. W. Lauterwasser ; Shaun D. Fontaine ; Hao Li ; Jiri Gut ; Kasiram Katneni ; Susan A. Charman ; Philip J. Rosenthal ; Matthew Bogyo ; Adam R. Renslo
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：6
• 期：11
• 页码：1145-1149
• 全文大小：298K
• ISSN：1948-5875

文摘

Peroxidic antimalarial agents including the sequiterpene artemisinins and the synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction of an endoperoxide bond. By chemically coupling this reduction to release of a tethered drug species it is possible to confer two distinct pharmacological effects in a parasite-selective fashion, both in vitro and in vivo. Here we demonstrate the trioxolane-mediated delivery of the antimalarial agent mefloquine in a mouse malaria model. Selective partitioning of the trioxolane鈥搈efloquine conjugate in parasitized erythrocytes, combined with effective exclusion of the conjugate from brain significantly reduced brain exposure as compared to mice directly administered mefloquine. These studies suggest the potential of trioxolane-mediated drug delivery to mitigate off-target effects of existing drugs, including the adverse neuropsychiatric effects of mefloquine use in therapeutic and chemoprophylactic settings.