Chemoprophylactic Agents in Schistosomiasis: Active and Inactive Terpenes

Gilbert, Benjamin; Souza, de; Cc, Fortes; Santos, Denis Amilton dos; Seabra, A. Do Prado; Kitagawa, Masaatsu; Pellegrino, J.

doi:10.2307/3277692

Cited by 16 publications

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“…Further interrogation of the chemical diversity found in plants suggests that terpenoids (terpenes) are the most abundant and numerous of the plant secondary products and they possess features, including considerable structural variation [ 20 ], that may be exploitable as next-generation anthelmintics. In clear support of this, previous studies have demonstrated that topical terpenoid application to the skin effectively prevents schistosome penetration, providing an innovative chemoprophylactic method to avert schistosomiasis [ 21 , 22 ]. However, it is presently unclear how terpenoids affect schistosome biology or, indeed, if they have activity against other parasitic trematodes, including F .…”

Section: Introductionmentioning

confidence: 78%

“…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 ).…”

Section: Resultsmentioning

confidence: 99%

“…hepatica parasites. Although these findings add value to the growing medicinal properties described for diterpenoids [ 54 – 56 ] and expand upon their anti-schistosomal chemoprophylactic characteristics [ 21 , 22 ], improving their selective potency is a necessary next step in their development as wide-acting anthelmintics. Whilst defining a specific mechanism of 7-keto-sempervirol action and experimental animal model verification was beyond the scope of this investigation, our results suggest that membrane biogenesis/maintenance and calcium homeostasis/stress are likely contributing to the diverse in vitro phenotypes observed in both fluke species.…”

Section: Discussionmentioning

confidence: 99%

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The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica

et al. 2015

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BackgroundTwo 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 FindingsHere 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/ Significance7-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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Section: Introductionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica

et al. 2015

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“…The anticercarial activity appeared to be due to the presence of trans-(-)-14,15-epoxygeranylgeraniol. Further investigations [163] have indicated that although a variety of terpenoids are active as prophylactic agents, this phenomenon is relatively rare, and no simple structure-activity relationship appears to be evident [164]. It is believed that if protection occurs, a simple physical barrier is not involved [164].…”

Section: (C) Chemoprophylaxismentioning

confidence: 97%

Progress in the Experimental Chemotherapy of Helminth Infections; Part I, Trematode and Cestode Infections

Islip

1973

Progress in Drug Research / Fortschritte Der Arzneimittelforschung / Progrès Des Recherches Pharmaceutiques

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“…Risedronate and its analogs are compounds that are used in human and veterinary clinics for prevention and treatment of osteoporosis, but in trypanosomatids and apicomplexan parasites, these compounds have been shown to be effective as FPP/GGPP synthase inhibitors and affect the calciosomes [123,124,125,126,127,128]. Several terpenes of essential oils, such as nerolidol or farnesol, appear to have growth inhibitory activity in different species, including apicomplexan and trypanosomatid parasites [129,130,131,132,133]. Some authors have suggested that these effects are due to the structural similarity of these compounds to prenyltransferase/synthase substrates, with which the abovementioned terpenes could compete [128,129,130,131,132].…”

Section: Biosynthesis Of Aromatic and Isoprenic Precursors Of Prenmentioning

confidence: 99%

Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

et al. 2019

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Human parasitic protozoa cause a large number of diseases worldwide and, for some of these diseases, there are no effective treatments to date, and drug resistance has been observed. For these reasons, the discovery of new etiological treatments is necessary. In this sense, parasitic metabolic pathways that are absent in vertebrate hosts would be interesting research candidates for the identification of new drug targets. Most likely due to the protozoa variability, uncertain phylogenetic origin, endosymbiotic events, and evolutionary pressure for adaptation to adverse environments, a surprising variety of prenylquinones can be found within these organisms. These compounds are involved in essential metabolic reactions in organisms, for example, prevention of lipoperoxidation, participation in the mitochondrial respiratory chain or as enzymatic cofactors. This review will describe several prenylquinones that have been previously characterized in human pathogenic protozoa. Among all existing prenylquinones, this review is focused on ubiquinone, menaquinone, tocopherols, chlorobiumquinone, and thermoplasmaquinone. This review will also discuss the biosynthesis of prenylquinones, starting from the isoprenic side chains to the aromatic head group precursors. The isoprenic side chain biosynthesis maybe come from mevalonate or non-mevalonate pathways as well as leucine dependent pathways for isoprenoid biosynthesis. Finally, the isoprenic chains elongation and prenylquinone aromatic precursors origins from amino acid degradation or the shikimate pathway is reviewed. The phylogenetic distribution and what is known about the biological functions of these compounds among species will be described, as will the therapeutic strategies associated with prenylquinone metabolism in protozoan parasites.

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Chemoprophylactic Agents in Schistosomiasis: Active and Inactive Terpenes

Cited by 16 publications

References 0 publications

The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica

The Diterpenoid 7-Keto-Sempervirol, Derived from Lycium chinense, Displays Anthelmintic Activity against both Schistosoma mansoni and Fasciola hepatica

Progress in the Experimental Chemotherapy of Helminth Infections; Part I, Trematode and Cestode Infections

Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

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