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.
authors.affiliation: La Trobe Institute for Molecular Science, La Trobe University , Melbourne, Victoria 3086, Australia.|Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Swapna
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rahmani
authors.affiliation: Burnet Institute , 85 Commercial Rd, Melbourne Victoria 3004, Australia.|Central Clinical School and Department of Microbiology, Monash University , Melbourne, Victoria 3004, Australia.
authors.forename: Damien R
authors.initials: DR
authors.lastname: Drew
authors.affiliation: Walter and Eliza Hall Institute , 1G Royal Parade, Parkville, Victoria 3052, Australia.|The Department of Medical Biology, The University of Melbourne , Melbourne, Victoria 3010, Australia.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Williams
authors.affiliation: Department of Life Sciences, Imperial College London , South Kensington SW7 2AZ, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Wilkinson
authors.affiliation: Walter and Eliza Hall Institute , 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Life Sciences, Imperial College London , South Kensington SW7 2AZ, United Kingdom.
authors.forename: Yan Hong
authors.initials: YH
authors.lastname: Tan
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , St Lucia, Queensland 4072, Australia.
authors.forename: Johnny X
authors.initials: JX
authors.lastname: Huang
authors.affiliation: Walter and Eliza Hall Institute , 1G Royal Parade, Parkville, Victoria 3052, Australia.|The Department of Medical Biology, The University of Melbourne , Melbourne, Victoria 3010, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Tonkin
authors.affiliation: Burnet Institute , 85 Commercial Rd, Melbourne Victoria 3004, Australia.|Central Clinical School and Department of Microbiology, Monash University , Melbourne, Victoria 3004, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.affiliation: Walter and Eliza Hall Institute , 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Life Sciences, Imperial College London , South Kensington SW7 2AZ, United Kingdom.
authors.forename: Jake
authors.initials: J
authors.lastname: Baum
authors.affiliation: La Trobe Institute for Molecular Science, La Trobe University , Melbourne, Victoria 3086, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D053778:Thiazolidines; C037068:latrunculin B; C037067:latrunculin A