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

• Published in: Journal of medicinal chemistry Vol. 59; no. 24; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.12.2016; Amer Chemical Soc
• Subjects: Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Chemistry, Medicinal; Dose-Response Relationship, Drug; Humans; Life Sciences & Biomedicine; Malaria - drug therapy; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Plasmodium falciparum - cytology; Plasmodium falciparum - drug effects; Plasmodium falciparum - metabolism; Science & Technology; Structure-Activity Relationship; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - pharmacology; IN-VITRO; ANALOGS; NATURAL-PRODUCTS; DRUG DISCOVERY; TOXOPLASMA; MALARIA; PROTEINS; CANCER; TOOLS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01109

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.