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.

Applying a Chemogeographic Strategy for Natural Product Discovery from the Marine Cyanobacterium Moorena bouillonii

“…genomes, on average [ 8 , 9 , 10 ]. Consistent with this finding, some 70 different isolated and structurally defined compounds have been reported from M. bouillonii ( Table S1 ) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. These display a broad structural diversity, and include peptides [ 41 ], cyclodepsipeptides [ 16 ], macrolides [ 12 ] and glycosidic macrolides [ 35 ], and lipids [ 43 ].…”

Bioactivities of Lyngbyabellins from Cyanobacteria of Moorea and Okeania Genera

“…Compounds 1 and 7 were active towards the malaria parasite (IC 50 1.1 and 0.3 μM, respectively), while 6 was moderately active (IC 50 6.4 μM). The antiplasmodial activity of compound 7 is less potent than what was reported by Sweeney-Jones et al [ 13 ]. This is presumably because compound 7 exhibits a better inhibition towards the liver stage of Plasmodium compared to the intraerythrocytic stage used in this research.…”

“…Indeed, as previously reported, cyclic structures with a side chain are the most cytotoxic [ 12 , 25 ]. Lyngbyabellins are known as actin-disrupting agents, and therefore, act on the cellular microfilaments network [ 12 , 13 , 26 , 27 ]. This disruption leads to the impossibility of cells to enter mitosis, giving abnormal cells with two nuclei.…”

“…Lyngbyabellins G, O, and P have recently been shown to inhibit the settlement of Amphibalanus amphitrite barnacle larvae. At the same time, such compounds are reported as antimalarial agents [ 13 ]. The number of marine natural products which were tested against Plasmodium is limited but increasing.…”

“…Other compounds showing promising activity against different types and stages of malaria were also isolated from cyanobacteria such as dolastatin 15, gallinamide A, hoshinoamide A, carmabin A, dragomabin, venturamide A, and companeramide A [ 15 , 16 , 17 , 18 , 19 , 20 ]. Moorea and Okeania genera already provided several antimalarial molecules, including mabunamide, ikoamide, kakeromamide B, ulongamide A, lyngbyabellin A, and bastimolides A and B [ 13 , 21 , 22 , 23 , 24 ].…”