Truncated latrunculins as actin inhibitors targeting Plasmodium falciparum motility and host cell invasion

Swapna Johnson, Raphael Rahmani, Damien R. Drew, Melanie J. Williams, Mark I Wilkinson, Yan Hong Tan, Johnny X. Huang, Christopher J. Tonkin, James Beeson, Jake Baum, Brian J Smith, Jonathan Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Polymerization of the cytosolic protein actin is critical to cell movement and host cell invasion by the malaria parasite, Plasmodium falciparum. Any disruption to actin polymerization dynamics will render the parasite incapable of invading a host cell and thereby unable to cause infection. Here, we explore the potential of using truncated latrunculins as potential chemotherapeutics for the treatment of malaria. Exploration of the binding interactions of the natural actin inhibitor latrunculins with actin revealed how a truncated core of the inhibitor could retain its key interaction features with actin. This truncated core was synthesized and subjected to preliminary structure-activity relationship studies to generate a focused set of analogues. Biochemical analyses of these analogues demonstrate their 6-fold increased activity compared with that of latrunculin B against P. falciparum and a 16-fold improved selectivity ex vivo. These data establish the latrunculin core as a potential focus for future structure-based drug design of chemotherapeutics against malaria.

Original languageEnglish
Pages (from-to)10994-11005
Number of pages12
JournalJournal of Medicinal Chemistry
Volume59
Issue number24
DOIs
Publication statusPublished - 22 Dec 2016

Cite this

Johnson, Swapna ; Rahmani, Raphael ; Drew, Damien R. ; Williams, Melanie J. ; Wilkinson, Mark I ; Tan, Yan Hong ; Huang, Johnny X. ; Tonkin, Christopher J. ; Beeson, James ; Baum, Jake ; Smith, Brian J ; Baell, Jonathan. / Truncated latrunculins as actin inhibitors targeting Plasmodium falciparum motility and host cell invasion. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 24. pp. 10994-11005.
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title = "Truncated latrunculins as actin inhibitors targeting Plasmodium falciparum motility and host cell invasion",
abstract = "Polymerization of the cytosolic protein actin is critical to cell movement and host cell invasion by the malaria parasite, Plasmodium falciparum. Any disruption to actin polymerization dynamics will render the parasite incapable of invading a host cell and thereby unable to cause infection. Here, we explore the potential of using truncated latrunculins as potential chemotherapeutics for the treatment of malaria. Exploration of the binding interactions of the natural actin inhibitor latrunculins with actin revealed how a truncated core of the inhibitor could retain its key interaction features with actin. This truncated core was synthesized and subjected to preliminary structure-activity relationship studies to generate a focused set of analogues. Biochemical analyses of these analogues demonstrate their 6-fold increased activity compared with that of latrunculin B against P. falciparum and a 16-fold improved selectivity ex vivo. These data establish the latrunculin core as a potential focus for future structure-based drug design of chemotherapeutics against malaria.",
author = "Swapna Johnson and Raphael Rahmani and Drew, {Damien R.} and Williams, {Melanie J.} and Wilkinson, {Mark I} and Tan, {Yan Hong} and Huang, {Johnny X.} and Tonkin, {Christopher J.} and James Beeson and Jake Baum and Smith, {Brian J} and Jonathan Baell",
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Johnson, S, Rahmani, R, Drew, DR, Williams, MJ, Wilkinson, MI, Tan, YH, Huang, JX, Tonkin, CJ, Beeson, J, Baum, J, Smith, BJ & Baell, J 2016, 'Truncated latrunculins as actin inhibitors targeting Plasmodium falciparum motility and host cell invasion', Journal of Medicinal Chemistry, vol. 59, no. 24, pp. 10994-11005. https://doi.org/10.1021/acs.jmedchem.6b01109

Truncated latrunculins as actin inhibitors targeting Plasmodium falciparum motility and host cell invasion. / Johnson, Swapna; Rahmani, Raphael; Drew, Damien R.; Williams, Melanie J.; Wilkinson, Mark I; Tan, Yan Hong; Huang, Johnny X.; Tonkin, Christopher J.; Beeson, James; Baum, Jake; Smith, Brian J; Baell, Jonathan.

In: Journal of Medicinal Chemistry, Vol. 59, No. 24, 22.12.2016, p. 10994-11005.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Johnson, Swapna

AU - Rahmani, Raphael

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AU - Tan, Yan Hong

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