Fascioliasis, a neglected foodborne disease caused by liver flukes (genus Fasciola), affects more than 200 million people worldwide. Despite technological advances, little is known about the molecular biology and biochemistry of these flukes. We present the draft genome of Fasciola gigantica for the first time. The assembled draft genome has a size of ∼1.04 Gb with an N50 and N90 of 129 and 149 kb, respectively. A total of 20 858 genes were predicted. The de novo repeats identified in the draft genome were 46.85%. The pathway included all of the genes of glycolysis, Krebs cycle, and fatty acid metabolism but lacked the key genes of the fatty acid biosynthesis pathway. This indicates that the fatty acid required for survival of the fluke may be acquired from the host bile. It may be hypothesized that the relatively larger F. gigantica genome did not evolve through genome duplications but rather is interspersed with many repetitive elements. The genomic information will provide a comprehensive resource to facilitate the development of novel interventions for fascioliasis control.

Opisthorchis felineus is the etiological agent of opisthorchiasis in humans. O. felineus cytochrome P450 (OfCYP450) is an important enzyme in the parasite xenobiotic metabolism. To identify the potential anti-opisthorchid compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,65,869) against the OfCYP450. The ligands were screened against OfCYP450 in four sequential docking modes that resulted in 361 ligands having better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 10 compounds were found to fit well with re-docking studies. After refinement by docking and drug-likeness analyses, four potential inhibitors (ZINC2358298, ZINC8790946, ZINC70707116, and ZINC85878789) were identified. These ligands with reference compounds (itraconazole and fluconazole) were further subjected to molecular dynamics simulation (MDS) and binding energy analyses to compare the dynamic structure of protein after ligand binding and the stability of the OfCYP450 and bound complexes. The binding energy analyses were also calculated. The results suggested that the compounds had a negative binding energy with -259.41, -110.09, -188.25, -163.30, -202.10, and -158.79 kJ mol for itraconazole, fluconazole, and compounds with IDs ZINC2358298, ZINC8790946, ZINC70707116, and ZINC85878789, respectively. These lead compounds displayed significant pharmacological and structural properties to be drug candidates. On the basis of MDS results and binding energy analyses, we concluded that ZINC8790946, ZINC70707116, and ZINC85878789 have excellent potential to inhibit OfCYP450.

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The liver fluke zoonoses, Fasciola spp. are parasitic helminths infecting humans and animals globally. Recent sequencing of the genome of Fasciola gigantica has provided a basis to understand the biochemistry of this parasite. Here, we identified the cytosolic malate dehydrogenase in F. gigantica (FgMDH) and characterized the enzyme biochemically and structurally. F. gigantica encodes a single cytosolic MDH, a key enzyme of the citric acid cycle. It catalyzes the reversible oxidation of malate to oxaloacetate using NAD +. The Fgmdh gene was amplified and cloned for expression of the recombinant protein. The purified protein showed a molecular weight of ~ 36 kDa that existed in a dimeric form in solution. The recombinant enzyme was catalytically active as it catalyzed both forward and reverse reactions efficiently. The kinetic parameters were determined for both directions. The structure of FgMDH and human MDH were modeled and validated. The superimposition of both the model structures showed overall structural similarity in the active site loop region, however, the conformation of the residues was different. Molecular docking elucidated the binding sites and affinities of the substrates and cofactors to the enzyme. Simulation of molecular dynamics and principal component analysis indicated the stability of the systems and collective motions, respectively. Understanding the structural and functional properties of MDH is important to better understand the roles of this enzyme in the biochemistry of the parasite. Two parasitic liver flukes, Fasciola gigantica and Fasciola hepatica are responsible for fascioliasis-a severe zoonotic disease that is financially detrimental to the global livestock industry 1. WHO classifies fascioliasis as a neglected tropical disease of economic importance 2. It is a major foodborne disease caused by the consumption of food/water contaminated with the parasites in their larval stage. It is primarily a veterinary disease that infects a variety of livestock, especially goat, sheep, and cattle 3-5 ; globally, over 600 million animals are affected by these flukes, resulting in loss of > US$3 billion p.a. F. gigantica is prevalent in tropical regions, including Africa and South and Southeast Asia, while F. hepatica is mostly found in temperate areas, including Europe, North and South America, and Australia 6. F. gigantica infects nearly 25-100% cattle annually in Africa, the Middle East, Southeast Asia, and other temperate countries 7. The global prevalence of fascioliasis is increasing in humans. As reported by WHO, nearly 180 million people are at risk, while 2.4-17 million people are infected globally 8. Human fascioliasis is primarily defined to Africa, Europe, the Middle East (including Egypt), Southeast Asia, and Latin America with the highest prevalence in Bolivian Plateau 9,10. The common symptoms of fascioliasis are enlarged liver and spleen, arthralgias, facial swelling, fever, abdominal pain, eosinophilia, and eggs in stool 11. The only drug of choice recommended by WHO is tricla...

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Species of the blood fluke Schistosoma are responsible for schistosomiasis, the second most common parasitic disease, which is prevalent particularly in poor communities. Under redox pressure, schistosomes survive in mammalian hosts with the help of thioredoxin glutathione reductase, which is an essential selenoenzyme. A recent study identified compounds with extremely potent antischistosome activity. Most importantly, certain compounds were active against all major schistosomes across different life cycle stages, where even praziquantel, the drug of choice, fails. The data offer compounds that exceed WHO standards for leads for schistosomiasis therapy activity. The work may serve as the basis for the development of new antischistosome compounds.

Fascioliasis is a neglected food-borne disease caused by liver flukes (genus Fasciola) and affects more than 200 million people worldwide. Despite technological advances, little is known about the molecular biology and biochemistry of the fluke. We present the draft genome of Fasciola gigantica for the first time. The assembled draft genome has a size of ~1.04 Gb with an N50 of 129 kb. A total of 20,858 genes were predicted. The de novo repeats identified in the draft genome were 46.85%. In pathway analysis, all the genes of glycolysis, Kreb's cycle and fatty acid metabolism were found to be present, but the key genes for fatty acid production in fatty acid biosynthesis were missing. This indicates that the fatty acid required for the survival of the fluke may be acquired from the host bile. The genomic information will provide a comprehensive resource to facilitate the development of novel interventions for fascioliasis control.

No abstract