Truncated Latrunculins as Actin Inhibitors Targeting Plasmodium falciparum Motility and Host Cell Invasion

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-12, Vol.59 (24), p.10994-11005
Main Authors: Johnson, Swapna, Rahmani, Raphaël, Drew, Damien R, Williams, Melanie J, Wilkinson, Mark, Tan, Yan Hong, Huang, Johnny X, Tonkin, Christopher J, Beeson, James G, Baum, Jake, Smith, Brian J, Baell, Jonathan B
Format: Article
Language:English
Subjects:
Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic - chemistry
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Dose-Response Relationship, Drug
Humans
Malaria - drug therapy
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum - cytology
Plasmodium falciparum - drug effects
Plasmodium falciparum - metabolism
Structure-Activity Relationship
Thiazolidines - chemical synthesis
Thiazolidines - chemistry
Thiazolidines - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01109