Potential of Lichen Secondary Metabolites against Plasmodium Liver Stage Parasites with FAS-II as the Potential Target

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• 作者：Ina L. Lauinger ; Livia Vivas ; Remo Perozzo ; Christopher Stairiker ; Alice Tarun ; Mire Zloh ; Xujie Zhang ; Hua Xu ; Peter J. Tonge ; Scott G. Franzblau ; Duc-Hung Pham ; Camila V. Esguerra ; Alexander D. Crawford ; Louis Maes ; Deniz Tasdemir
• 刊名：Journal of Natural Products
• 出版年：2013
• 出版时间：June 28, 2013
• 年：2013
• 卷：76
• 期：6
• 页码：1064-1070
• 全文大小：324K
• 年卷期：v.76,no.6(June 28, 2013)
• ISSN：1520-6025

文摘

Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC₅₀ value 2.3 渭M, BS IC₅₀ value 47.3 渭M). The compounds 1鈥?b>3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1鈥?b>4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.