Development Of Antischistosomal Drugs Research Articles

The Idiosyncratic Efficacy of Spironolactone-Loaded PLGA Nanoparticles Against Murine Intestinal Schistosomiasis.

Schistosomiasis is a chronic debilitating parasitic disease accompanied with severe mortality rates. Although praziquantel (PZQ) acts as the sole drug for the management of this disease, it has many limitations that restrict the use of this treatment approach. Repurposing of spironolactone (SPL) and nanomedicine represents a promising approach to improve anti-schistosomal therapy. We have developed SPL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to enhance the solubility, efficacy, and drug delivery and hence decrease the frequency of administration, which is of great clinical value. The physico-chemical assessment was performed starting with particle size analysis and confirmed using TEM, FT-IR, DSC, and XRD. The antischistosomal effect of the SPL-loaded PLGA NPs against Schistosoma mansoni (S. mansoni)-induced infection in mice was also estimated. Our results manifested that the optimized prepared NPs had particle size of 238.00 ± 7.21 nm, and the zeta potential was -19.66 ± 0.98 nm, effective encapsulation 90.43±8.81%. Other physico-chemical features emphasized that nanoparticles were completely encapsulated inside the polymer matrix. The in vitro dissolution studies revealed that SPL-loaded PLGA NPs showed sustained biphasic release pattern and followed Korsmeyer-Peppas kinetics corresponding to Fickian diffusion (n<0.45). The used regimen was efficient against S. mansoni infection and induced significant reduction in spleen, liver indices, and total worm count (ρ<0.05). Besides, when targeting the adult stages, it induced decline in the hepatic egg load and the small intestinal egg load by 57.75% and 54.17%, respectively, when compared to the control group. SPL-loaded PLGA NPs caused extensive damage to adult worms on tegument and suckers, leading to the death of the parasites in less time, plus marked improvement in liver pathology. Collectively, these findings provided proof-of-evidence that the developed SPL-loaded PLGA NPs could be potentially used as a promising candidate for new antischistosomal drug development.

Disulfiram and dithiocarbamate analogues demonstrate promising antischistosomal effects

Schistosomiasis is a neglected tropical disease with more than 200 million new infections per year. It is caused by parasites of the genus Schistosoma and can lead to death if left untreated. Currently, only two drugs are available to combat schistosomiasis: praziquantel and, to a limited extent, oxamniquine. However, the intensive use of these two drugs leads to an increased probability of the emergence of resistance. Thus, the search for new active substances and their targeted development are mandatory. In this study the substance class of “dithiocarbamates” and their potential as antischistosomal agents is highlighted. These compounds are derived from the basic structure of the human aldehyde dehydrogenase inhibitor disulfiram (tetraethylthiuram disulfide, DSF) and its metabolites. Our compounds revealed promising activity (in vitro) against adults of Schistosoma mansoni, such as the reduction of egg production, pairing stability, vitality, and motility. Moreover, tegument damage as well as gut dilatations or even the death of the parasite were observed. We performed detailed structure-activity relationship studies on both sides of the dithiocarbamate core leading to a library of approximately 300 derivatives (116 derivatives shown here). Starting with 100 μm we improved antischistosomal activity down to 25 μm by substitution of the single bonded sulfur atom for example with different benzyl moieties and integration of the two residues on the nitrogen atom into a cyclic structure like piperazine. Its derivatization at the 4-nitrogen with a sulfonyl group or an acyl group led to the most active derivatives of this study which were active at 10 μm. In light of this SAR study, we identified 17 derivatives that significantly reduced motility and induced several other phenotypes at 25 μm, and importantly five of them have antischistosomal activity also at 10 μm. These derivatives were found to be non-cytotoxic in two human cell lines at 100 μm. Therefore, dithiocarbamates seem to be interesting new candidates for further antischistosomal drug development.

Schistosomiasis mansoni: A new therapeutic target for ubiquinol, a natural inhibitor of neutral magnesium-dependent sphingomyelinase in murine model.

Constituting the host-parasite interface and playing a censorious role in host immune response modulation and parasite survival, tegument represents a crucial target for many antischistosomal drugs. Sphingomyelin forms a stable outer leaflet of tegumental membrane-lipid bilayer. Neutral magnesium‏-dependent sphingomyelinase (Mg2+-nSMase) is a key enzyme in sphingomyelin breakdown was identified in schistosomes. We investigated the in vivo efficacy of ubiquinol, a natural inhibitor of Mg2+-nSMase, in free and niosomes-encapsulated forms, through five-day and 15-day regimens on the early and late Schistosoma mansoni parasitic stages, respectively, compared to PZQ. Oral administration of 300 mg/kg/day ubiquinol-encapsulated niosomes (U-N) showed significant deterioration of the parasitic growth and development in the term of reduction of lung schistosomula burden (39.12%), adult worm burden (50.81%), hepatic and intestinal tissue-egg counts (80.89% and 75.54%, respectively). PZQ and free ubiquinol regimens reported reductions in lung schistosomula counts (45.36% and 22.90%, respectively) and total worm burdens of 86.28% and 24.58%, respectively. U-N therapy revealed worms de-pairing and remarkable diminution in female worms’ perimeters and fecundity. Scanning electron microscope revealed disruption of tegumental ridges with excessive longitudinal corrugation. Transmission electron microscope showed testicular and ovarian parenchymal degeneration, signs of immaturity and cell apoptosis. Indirect immunofluorescence assay approved parasite's tegumental changes. Remarkable reduction of granulomas size with amelioration of hepatic pathology and fibrosis were assumed to be attributed to the anti-inflammatory and anti-oxidant properties of ubiquinol. These findings with the drug safety profile suggest that U-N could be a promising candidate for a new antischistosomal drug development.

Closing the Gap: An Atomistic Structural and Functional Perspective of S. mansoni Universal Stress G4LZI3 Protein in Complex with Phenolic Compounds.

For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 Stress Protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified 'lead' molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. This study therefore, implemented the use of Molecular Dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4- ZLI3 to these key phenolic compounds. Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

Effect of Praziquantel on Schistosoma mekongi Proteome and Phosphoproteome.

Schistosoma mekongi causes schistosomiasis in southeast Asia, against which praziquantel (PZQ) is the only treatment option. PZQ resistance has been reported, thus increasing the requirement to understand mechanism of PZQ. Herein, this study aimed to assess differences in proteome and phosphoproteome of S. mekongi after PZQ treatment for elucidating its action. Furthermore, key kinases related to PZQ effects were predicted to identify alternative targets for novel drug development. Proteomes of S. mekongi were profiled after PZQ treatment at half maximal inhibitory concentration and compared with untreated worms. A total of 144 proteins were differentially expressed after treatment. In parallel, immunohistochemistry indicated a reduction of phosphorylation, with 43 phosphoproteins showing reduced phosphorylation, as identified by phosphoproteomic approach. Pathway analysis of mass spectrometric data showed that calcium homeostasis, worm antigen, and oxidative stress pathways were influenced by PZQ treatment. Interestingly, two novel mechanisms related to protein folding and proteolysis through endoplasmic reticulum-associated degradation pathways were indicated as a parasiticidal mechanism of PZQ. According to kinase–substrate predictions with bioinformatic tools, Src kinase was highlighted as the major kinase related to the alteration of phosphorylation by PZQ. Interfering with these pathways or applying Src kinase inhibitors could be alternative approaches for further antischistosomal drug development.

Praziquantel derivatives exhibit activity against both juvenile and adult Schistosoma japonicum

A praziquantel analog 10-hydroxy praziquantel and eight praziquantel/peroxide conjugates were synthesized. The biological activity of these compounds was evaluated against juvenile and adult stages of Schistosoma japonicum. Unlike praziquantel, 10-hydroxy praziquantel exhibits activity against both juvenile and adult Schistosoma japonicumin. All hybrid compounds displayed modest to significant worm killing activity. The present study has important significance for the development of hybrid antischistosomal drugs.

Harnessing the wealth of Chinese scientific literature: schistosomiasis research and control in China

The economy of China continues to boom and so have its biomedical research and related publishing activities. Several so-called neglected tropical diseases that are most common in the developing world are still rampant or even emerging in some parts of China. The purpose of this article is to document the significant research potential from the Chinese biomedical bibliographic databases. The research contributions from China in the epidemiology and control of schistosomiasis provide an excellent illustration. We searched two widely used databases, namely China National Knowledge Infrastructure (CNKI) and VIP Information (VIP). Employing the keyword "Schistosoma" () and covering the period 1990–2006, we obtained 10,244 hits in the CNKI database and 5,975 in VIP. We examined 10 Chinese biomedical journals that published the highest number of original research articles on schistosomiasis for issues including languages and open access. Although most of the journals are published in Chinese, English abstracts are usually available. Open access to full articles was available in China Tropical Medicine in 2005/2006 and is granted by the Chinese Journal of Parasitology and Parasitic Diseases since 2003; none of the other journals examined offered open access. We reviewed (i) the discovery and development of antischistosomal drugs, (ii) the progress made with molluscicides and (iii) environmental management for schistosomiasis control in China over the past 20 years. In conclusion, significant research is published in the Chinese literature, which is relevant for local control measures and global scientific knowledge. Open access should be encouraged and language barriers removed so the wealth of Chinese research can be more fully appreciated by the scientific community.

Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins

Remarkable achievements have been made in the control of schistosomiasis in China, with chemotherapy playing a seminal role. From the early 1950s through the early 1980s, Chinese scientists made considerable progress in discovery and development of compounds with antischistosomal properties, including antimonials, non-antimonials and various effective principles stemming from traditional herbs. However, only few compounds entered clinical testing, while others were abandoned mainly due to their toxicity and poor efficacy. The advent of praziquantel in the 1970s changed the landscape of research and development of drugs for treatment and morbidity control of schistosomiasis. The main Chinese contributions to enhance the understanding of the antischistosomal drug praziquantel are reviewed here, including issues of metabolism, antibody-dependency, host immune factors, stage-specific susceptibility and resistance. Over the past 25 years, researchers from China successfully developed artemether and artesunate, two derivatives from the antimalarial artemisinin, as promising drugs against Schistosoma japonicum. Laboratory investigations showed that the artemisinins display their highest activity against the juvenile stages of the parasite. These findings were consistently confirmed in randomised controlled trials; repeated oral administration of artemether or artesunate was safe and efficacious in the prevention of patent S. japonicum infections. The key findings are reviewed here, and emphasis is placed on how it stimulated research outside of China on other human schistosome species.