Trioxolane-mediated delivery of mefloquine limits brain exposure in a mouse model of malaria

Erica M W Lauterwasser, Shaun D Fontaine, Hao Li, Jiri Gut, Kasiram Katneni, Susan Ann Charman, Philip J Rosenthal, Matthew Bogyo, Adam R Renslo

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-mefloquine 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.
Original languageEnglish
Pages (from-to)1145-1149
Number of pages5
JournalA C S Medicinal Chemistry Letters
Volume6
Issue number11
DOIs
Publication statusPublished - 2015

Keywords

  • antimalarial
  • trioxolane
  • mefloquine
  • drug delivery

Cite this

Lauterwasser, Erica M W ; Fontaine, Shaun D ; Li, Hao ; Gut, Jiri ; Katneni, Kasiram ; Charman, Susan Ann ; Rosenthal, Philip J ; Bogyo, Matthew ; Renslo, Adam R. / Trioxolane-mediated delivery of mefloquine limits brain exposure in a mouse model of malaria. In: A C S Medicinal Chemistry Letters. 2015 ; Vol. 6, No. 11. pp. 1145-1149.
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abstract = "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-mefloquine 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.",
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Lauterwasser, EMW, Fontaine, SD, Li, H, Gut, J, Katneni, K, Charman, SA, Rosenthal, PJ, Bogyo, M & Renslo, AR 2015, 'Trioxolane-mediated delivery of mefloquine limits brain exposure in a mouse model of malaria' A C S Medicinal Chemistry Letters, vol. 6, no. 11, pp. 1145-1149. https://doi.org/10.1021/acsmedchemlett.5b00296

Trioxolane-mediated delivery of mefloquine limits brain exposure in a mouse model of malaria. / Lauterwasser, Erica M W; Fontaine, Shaun D; Li, Hao; Gut, Jiri; Katneni, Kasiram; Charman, Susan Ann; Rosenthal, Philip J; Bogyo, Matthew; Renslo, Adam R.

In: A C S Medicinal Chemistry Letters, Vol. 6, No. 11, 2015, p. 1145-1149.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Fontaine, Shaun D

AU - Li, Hao

AU - Gut, Jiri

AU - Katneni, Kasiram

AU - Charman, Susan Ann

AU - Rosenthal, Philip J

AU - Bogyo, Matthew

AU - Renslo, Adam R

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