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

Abstract

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 μM, BS IC50 value 47.3 μM). The compounds 1-3 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, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modelling 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.

In vitroantitumor activities of the lichen compounds olivetoric, physodic and psoromic acid in rat neuron and glioblastoma cells

“…Another study on the protective effect of PSA was carried out on mice and the gastric protective effect of PSA was determined (Sepulveda et al 2013). In the studies related with toxic concentrations of PSA, inhibition of growth as determined in different bacteria species (Celenza et al 2013;Mitrović et al 2014), liver parasites (Lauinger et al 2013) and some cancer cells (Correcché et al 2004;Brandao et al 2013) exposed to PSA. In addition, Correcché et al (2004) revealed that PSA significantly showed apoptotic activity on hepatocytes.…”

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

“…Glycyrrhetic acid (Figure 4) has exhibited notable (IC50 1.69 μg/mL) in vitro antiplasmodial activity against P. falciparum, and docking studies (Discovery Studio) have also shown glycyrretic acid to dock moderately well to P. falciparum lactate dehydrogenase [414]. (+)-Usnic acid, a secondary metabolite from lichen, was identified as an active and selective inhibitor of the liver stage form of Plasmodium berghei by Lauinger and co-workers [415]. In the molecular docking study to identify the binding affinities and binding sites of (+)-usnic acid and three other lichen secondary metabolites (evernic acid, vulpic acid, and psoromic acid, Figure 16) with Plasmodium type II fatty acid biosynthesis pathway (FAS-II) enzymes, these workers found that the mechanism of action of lichen acids on FAS-II may be different from those of previously described FAS-II enzymes inhibitors.…”

“…The modeling study they carried out indicated that those compounds appear to inhibit FAS-II enzymes indirectly via binding to allosteric sites on the protein surface and not to the active sites of FAS-II enzymes. This indirect binding is speculated to possibly affect the enzyme conformations and subsequently interfere with the catalytic activities [415].…”

Usnik Asitin Broylerlerdeki Anticoccidial Etkinliği

“…It is shown to exert a number of biological activities including anti-inflammatory, analgesic and antipyretic, antibiotic, antiviral, antimicrobial, antiproliferative, gastroprotective, antitumor, antioxidant, antimycotic, antigrowth and antiinsect properties [22,23] . Although few studies [9,[24][25][26][27] dealing with antiprotozoal effect of usnic acid are available, its anticoccidial effect is largely unknown. The present experiment was set out to investigate therapeutic action of usnic acid against coccidiosis in broilers.…”

“…De Carvalho et al [24] investigated the effects of usnic acid against Trypanosoma cruzi epimastigotes and trypomastigotes, and reported that usnic acid treatment resulted in growth inhibition in a dose-dependent manner. Lauinger et al [26] reported antiplasmodial effect of some lichen compounds (e.g., evernic acid, vulpic acid, psoromic acid and (+)-usnic acid) against liver stages of Plasmodium berghei.…”