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The diterpenoid 7-keto-sempervirol, derived from Lycium chinense, displays anthelmintic activity against both Schistosoma mansoni and Fasciola hepatica.

Edwards J, Brown M, Peak E, Bartholomew B, Nash RJ, Hoffmann KF - PLoS Negl Trop Dis (2015)

Bottom Line: This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology.As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM).Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss. 7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, United Kingdom.

ABSTRACT

Background: Two platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control.

Methodology/ principle findings: Here we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 μM) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss.

Conclusions/ significance: 7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control.

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Related in: MedlinePlus

7-keto-sempervirol is a diterpenoid phenol derived from Lycium chinense.This compound possesses a diterpenoid (C20) (4 isoprene units) scaffold consisting of a single phenyl group, one hydroxyl group (red) and one carbonyl group (red). In light of Lipinski’s rule of 5 (RO5) [57], this compound only possesses one violation to the rule (log p > 5), however, three out of the four core rules are satisfied.
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pntd.0003604.g001: 7-keto-sempervirol is a diterpenoid phenol derived from Lycium chinense.This compound possesses a diterpenoid (C20) (4 isoprene units) scaffold consisting of a single phenyl group, one hydroxyl group (red) and one carbonyl group (red). In light of Lipinski’s rule of 5 (RO5) [57], this compound only possesses one violation to the rule (log p > 5), however, three out of the four core rules are satisfied.

Mentions: Due to the previously described action of select terpenes on schistosome viability [21,22] and definitive host penetration [37], we became interested in assessing the potential anthelmintic activity of 7-keto-sempervirol, a diterpenoid purified from Lycium chinense (Fig. 1). Employing the HFB [25], a titration series of 7-keto-sempervirol (100 μM–1.575 μM) was first used to assess the ability of this diterpenoid to affect schistosomula viability during in vitro co-culture (Fig. 2). At high 7-keto-sempervirol concentrations (100–25 μM), almost all of the schistosomula were killed or severely affected as indicated by low percent viability values (Fig. 2A) and fluorescent microscopic images of individual parasites (PI positive parasites > FDA positive parasites) (Fig. 2B). Lower 7-keto-sempervirol concentrations (between 6.25 μM–1.575 μM) had little effect on schistosomula viability and phenotype when compared to the DMSO control parasites. Based on these titration experiments, an LD50 of 19.1 μM was derived for 7-keto-sempervirol on the schistosomula lifecycle stage. A parallel set of titration experiments was additionally performed with the human HepG2 cell line (S1 Fig.) and demonstrated a 7-keto-sempervirol derived LD50 of 80 μM. 7-keto-sempervirol, therefore, demonstrates a therapeutic index of 4.2 towards the intra-mammalian schistosomula lifecycle stage.


The diterpenoid 7-keto-sempervirol, derived from Lycium chinense, displays anthelmintic activity against both Schistosoma mansoni and Fasciola hepatica.

Edwards J, Brown M, Peak E, Bartholomew B, Nash RJ, Hoffmann KF - PLoS Negl Trop Dis (2015)

7-keto-sempervirol is a diterpenoid phenol derived from Lycium chinense.This compound possesses a diterpenoid (C20) (4 isoprene units) scaffold consisting of a single phenyl group, one hydroxyl group (red) and one carbonyl group (red). In light of Lipinski’s rule of 5 (RO5) [57], this compound only possesses one violation to the rule (log p > 5), however, three out of the four core rules are satisfied.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358835&req=5

pntd.0003604.g001: 7-keto-sempervirol is a diterpenoid phenol derived from Lycium chinense.This compound possesses a diterpenoid (C20) (4 isoprene units) scaffold consisting of a single phenyl group, one hydroxyl group (red) and one carbonyl group (red). In light of Lipinski’s rule of 5 (RO5) [57], this compound only possesses one violation to the rule (log p > 5), however, three out of the four core rules are satisfied.
Mentions: Due to the previously described action of select terpenes on schistosome viability [21,22] and definitive host penetration [37], we became interested in assessing the potential anthelmintic activity of 7-keto-sempervirol, a diterpenoid purified from Lycium chinense (Fig. 1). Employing the HFB [25], a titration series of 7-keto-sempervirol (100 μM–1.575 μM) was first used to assess the ability of this diterpenoid to affect schistosomula viability during in vitro co-culture (Fig. 2). At high 7-keto-sempervirol concentrations (100–25 μM), almost all of the schistosomula were killed or severely affected as indicated by low percent viability values (Fig. 2A) and fluorescent microscopic images of individual parasites (PI positive parasites > FDA positive parasites) (Fig. 2B). Lower 7-keto-sempervirol concentrations (between 6.25 μM–1.575 μM) had little effect on schistosomula viability and phenotype when compared to the DMSO control parasites. Based on these titration experiments, an LD50 of 19.1 μM was derived for 7-keto-sempervirol on the schistosomula lifecycle stage. A parallel set of titration experiments was additionally performed with the human HepG2 cell line (S1 Fig.) and demonstrated a 7-keto-sempervirol derived LD50 of 80 μM. 7-keto-sempervirol, therefore, demonstrates a therapeutic index of 4.2 towards the intra-mammalian schistosomula lifecycle stage.

Bottom Line: This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology.As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM).Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss. 7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, United Kingdom.

ABSTRACT

Background: Two platyhelminths of biomedical and commercial significance are Schistosoma mansoni (blood fluke) and Fasciola hepatica (liver fluke). These related trematodes are responsible for the chronic neglected tropical diseases schistosomiasis and fascioliasis, respectively. As no vaccine is currently available for anti-flukicidal immunoprophylaxis, current treatment is mediated by mono-chemical chemotherapy in the form of mass drug administration (MDA) (praziquantel for schistosomiasis) or drenching (triclabendazole for fascioliasis) programmes. This overreliance on single chemotherapeutic classes has dramatically limited the number of novel chemical entities entering anthelmintic drug discovery pipelines, raising significant concerns for the future of sustainable blood and liver fluke control.

Methodology/ principle findings: Here we demonstrate that 7-keto-sempervirol, a diterpenoid isolated from Lycium chinense, has dual anthelmintic activity against related S. mansoni and F. hepatica trematodes. Using a microtiter plate-based helminth fluorescent bioassay (HFB), this activity is specific (Therapeutic index = 4.2, when compared to HepG2 cell lines) and moderately potent (LD50 = 19.1 μM) against S. mansoni schistosomula cultured in vitro. This anti-schistosomula effect translates into activity against both adult male and female schistosomes cultured in vitro where 7-keto-sempervirol negatively affects motility/behaviour, surface architecture (inducing tegumental holes, tubercle swelling and spine loss/shortening), oviposition rates and egg morphology. As assessed by the HFB and microscopic phenotypic scoring matrices, 7-keto-sempervirol also effectively kills in vitro cultured F. hepatica newly excysted juveniles (NEJs, LD50 = 17.7 μM). Scanning electron microscopy (SEM) evaluation of adult F. hepatica liver flukes co-cultured in vitro with 7-keto-sempervirol additionally demonstrates phenotypic abnormalities including breaches in tegumental integrity and spine loss.

Conclusions/ significance: 7-keto-sempervirol negatively affects the viability and phenotype of two related pathogenic trematodes responsible for significant human and animal infectious diseases. This plant-derived, natural product is also active against both larval and adult developmental forms. As such, the data collectively indicate that 7-keto-sempervirol is an important starting point for anthelmintic drug development. Medicinal chemistry optimisation of more potent 7-keto-sempervirol analogues could lead to the identification of novel chemical entities useful for future combinatorial or replacement anthelmintic control.

Show MeSH
Related in: MedlinePlus