Antimalarial Peptide and Polyketide Natural Products from the Fijian Marine Cyanobacterium Moorea producens

Abstract

A new cyclic peptide, kakeromamide B (1), and previously described cytotoxic cyanobacterial natural products ulongamide A (2), lyngbyabellin A (3), 18E-lyngbyaloside C (4), and lyngbyaloside (5) were identified from an antimalarial extract of the Fijian marine cyanobacterium Moorea producens. Compound 1 exhibited moderate activity against Plasmodium falciparum blood-stages with an EC50 value of 8.9 µM whereas 2 and 3 were more potent with EC50 values of 0.99 µM and 1.5 nM, respectively. Compounds 1, 4, and 5 displayed moderate liver-stage antimalarial activity against P. berghei liver schizonts with EC50 values of 11, 7.1, and 4.5 µM, respectively. The threading-based computational method FINDSITEcomb2.0 predicted the binding of 1 and 2 to potentially druggable proteins of Plasmodium falciparum, prompting formulation of hypotheses about possible mechanisms of action. Kakeromamide B (1) was predicted to bind to several Plasmodium actin-like proteins and a sortilin protein suggesting possible interference with parasite invasion of host cells. When 1 was tested in a mammalian actin polymerization assay, it stimulated actin polymerization in a dose-dependent manner, suggesting that 1 does, in fact, interact with actin.