期刊
MARINE DRUGS
卷 18, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/md18030167
关键词
marine; cyanobacteria; malaria; mechanism of action; natural product
资金
- International Cooperative Biodiversity Groups (ICBG) Grant from the U.S. National Institutes of Health [U19-TW007401]
- Bill AMP
- Melinda Gates Foundation, Seattle, WA [OPP1107194]
- Division of General Medical Sciences of the National Institutes of Health [1R35GM-118039]
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. Compounds 1 and 2 exhibited moderate activity against Plasmodium falciparum blood-stages with EC50 values of 0.89 and 0.99 mu M, respectively, whereas 3 was more potent with an EC50 value of 0.15 nM. Compounds 1, 4, and 5 displayed moderate liver-stage antimalarial activity against P. berghei liver schizonts with EC50 values of 1.1, 0.71, and 0.45 mu M, 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.
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