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1.
PLoS One ; 19(6): e0302390, 2024.
Article in English | MEDLINE | ID: mdl-38923997

ABSTRACT

Schistosomiasis is a neglected tropical disease which imposes a considerable and enduring impact on affected regions, leading to persistent morbidity, hindering child development, diminishing productivity, and imposing economic burdens. Due to the emergence of drug resistance and limited management options, there is need to develop additional effective inhibitors for schistosomiasis. In view of this, quantitative structure-activity relationship studies, molecular docking, molecular dynamics simulations, drug-likeness and pharmacokinetics predictions were applied to 39 Schistosoma mansoni Thioredoxin Glutathione Reductase (SmTGR) inhibitors. The chosen QSAR model demonstrated robust statistical parameters, including an R2 of 0.798, R2adj of 0.767, Q2cv of 0.681, LOF of 0.930, R2test of 0.776, and cR2p of 0.746, confirming its reliability. The most active derivative (compound 40) was identified as a lead candidate for the development of new potential non-covalent inhibitors through ligand-based design. Subsequently, 12 novel compounds (40a-40l) were designed with enhanced anti-schistosomiasis activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules. Furthermore, drug-likeness and pharmacokinetics prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for the treatment of schistosomiasis.


Subject(s)
Drug Design , Molecular Docking Simulation , Molecular Dynamics Simulation , Quantitative Structure-Activity Relationship , Schistosoma mansoni , Schistosomiasis , Schistosoma mansoni/drug effects , Ligands , Animals , Schistosomiasis/drug therapy , NADH, NADPH Oxidoreductases/antagonists & inhibitors , NADH, NADPH Oxidoreductases/chemistry , NADH, NADPH Oxidoreductases/metabolism , Humans , Multienzyme Complexes
2.
J Med Chem ; 67(12): 10076-10095, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38847803

ABSTRACT

The NAD+-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from Schistosoma mansoni (SmSirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and SmSirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.


Subject(s)
Oxadiazoles , Sirtuin 2 , Sirtuin 2/antagonists & inhibitors , Sirtuin 2/metabolism , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesis , Humans , Structure-Activity Relationship , Molecular Docking Simulation , Animals , Cell Line, Tumor , Cell Survival/drug effects , Schistosoma mansoni/drug effects , Schistosoma mansoni/enzymology , Cell Movement/drug effects
3.
Parasit Vectors ; 17(1): 279, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38943214

ABSTRACT

BACKGROUND: Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis. METHODS: This was an open-label, randomised clinical trial involving 426 school-aged children (7-15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment. RESULTS: Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni-infected children (n = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium-infected children (n = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported. CONCLUSIONS: A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes.


Subject(s)
Anthelmintics , Artemisinins , Artesunate , Drug Therapy, Combination , Praziquantel , Pyrimethamine , Schistosoma haematobium , Schistosoma mansoni , Schistosomiasis haematobia , Schistosomiasis mansoni , Humans , Child , Praziquantel/administration & dosage , Praziquantel/adverse effects , Praziquantel/therapeutic use , Pyrimethamine/administration & dosage , Pyrimethamine/therapeutic use , Pyrimethamine/adverse effects , Animals , Adolescent , Artesunate/administration & dosage , Artesunate/therapeutic use , Female , Male , Schistosomiasis mansoni/drug therapy , Schistosoma haematobium/drug effects , Schistosomiasis haematobia/drug therapy , Schistosoma mansoni/drug effects , Kenya , Artemisinins/administration & dosage , Artemisinins/therapeutic use , Artemisinins/adverse effects , Treatment Outcome , Anthelmintics/administration & dosage , Anthelmintics/adverse effects , Anthelmintics/therapeutic use , Sulfalene/administration & dosage , Sulfalene/therapeutic use , Sulfalene/adverse effects , Drug Combinations , Parasite Egg Count
4.
ACS Infect Dis ; 10(6): 1935-1948, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38757505

ABSTRACT

Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics.


Subject(s)
Cathepsin B , Schistosoma mansoni , Cathepsin B/antagonists & inhibitors , Cathepsin B/metabolism , Animals , Schistosoma mansoni/enzymology , Schistosoma mansoni/drug effects , Crystallography, X-Ray , Schistosomicides/pharmacology , Schistosomicides/chemistry , Protein Binding , Models, Molecular
5.
Antimicrob Agents Chemother ; 68(7): e0011424, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38780260

ABSTRACT

Schistosomiasis, a widespread parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, primarily in developing countries. Praziquantel, the sole drug currently approved for schistosomiasis treatment, demonstrates effectiveness against patent infections. A recent study highlighted the antiparasitic properties of amiodarone, an anti-arrhythmic drug, exhibiting higher efficacy than praziquantel against prepatent infections. This study assessed the efficacy of amiodarone and praziquantel, both individually and in combination, against Schistosoma mansoni through comprehensive in vitro and in vivo experiments. In vitro experiments demonstrated synergistic activity (fractional inhibitory concentration index ≤0.5) for combinations of amiodarone with praziquantel. In a murine model of schistosomiasis featuring prepatent infections, treatments involving amiodarone (200 or 400 mg/kg) followed by praziquantel (200 or 400 mg/kg) yielded a substantial reduction in worm burden (60%-70%). Given the low efficacy of praziquantel in prepatent infections, combinations of amiodarone with praziquantel may offer clinical utility in the treatment of schistosomiasis.


Subject(s)
Amiodarone , Praziquantel , Schistosoma mansoni , Schistosomiasis mansoni , Amiodarone/pharmacology , Amiodarone/therapeutic use , Animals , Praziquantel/pharmacology , Praziquantel/therapeutic use , Schistosoma mansoni/drug effects , Mice , Schistosomiasis mansoni/drug therapy , Schistosomiasis mansoni/parasitology , Female , Anthelmintics/pharmacology , Anthelmintics/therapeutic use , Drug Synergism , Drug Therapy, Combination , Male , Disease Models, Animal
6.
Parasitol Res ; 123(5): 215, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38771511

ABSTRACT

Schistosomiasis is a neglected tropical disease associated with considerable morbidity. Praziquantel (PZQ) is effective against adult schistosomes, yet, it has little effect on juvenile stages, and PZQ resistance is emerging. Adopting the drug repurposing strategy as well as assuming enhancing the efficacy and lessening the doses and side effects, the present study aimed to investigate the in vivo therapeutic efficacy of the widely used antiarrhythmic, amiodarone, and diuretic, spironolactone, and combinations of them compared to PZQ. Mice were infected by Schistosoma mansoni "S. mansoni" cercariae (Egyptian strain), then they were divided into two major groups: Early- [3 weeks post-infection (wpi)] and late- [6 wpi] treated. Each group was subdivided into seven subgroups: positive control, PZQ, amiodarone, spironolactone, PZQ combined with amiodarone, PZQ combined with spironolactone, and amiodarone combined with spironolactone-treated groups. Among the early-treated groups, spironolactone had the best therapeutic impact indicated by a 69.4% reduction of total worm burden (TWB), 38.6% and 48.4% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 49%. Whereas, among the late-treated groups, amiodarone combined with PZQ was superior to PZQ alone evidenced by 96.1% reduction of TWB with the total disappearance of female and copula in the liver and intestine, 53.1% and 84.9% reduction of liver and intestine egg load, and a significant reduction of liver granuloma number by 67.6%. Comparatively, spironolactone was superior to PZQ and amiodarone in the early treatment phase targeting immature stages, while amiodarone had a more potent effect when combined with PZQ in the late treatment phase targeting mature schistosomes.


Subject(s)
Amiodarone , Disease Models, Animal , Praziquantel , Schistosoma mansoni , Schistosomiasis mansoni , Animals , Schistosomiasis mansoni/drug therapy , Schistosomiasis mansoni/parasitology , Mice , Schistosoma mansoni/drug effects , Praziquantel/therapeutic use , Praziquantel/pharmacology , Amiodarone/therapeutic use , Amiodarone/pharmacology , Female , Spironolactone/therapeutic use , Spironolactone/pharmacology , Schistosomicides/therapeutic use , Schistosomicides/pharmacology , Male , Anthelmintics/therapeutic use , Anthelmintics/pharmacology , Treatment Outcome , Drug Therapy, Combination , Liver/parasitology
7.
Molecules ; 29(9)2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38731401

ABSTRACT

The burden of human schistosomiasis, a known but neglected tropical disease in Sub-Saharan Africa, has been worrisome in recent years. It is becoming increasingly difficult to tackle schistosomiasis with praziquantel, a drug known to be effective against all Schistosoma species, due to reports of reduced efficacy and resistance. Therefore, this study seeks to investigate the antischistosomal potential of phytochemicals from Azadirachta indica against proteins that have been implicated as druggable targets for the treatment of schistosomiasis using computational techniques. In this study, sixty-three (63) previously isolated and characterized phytochemicals from A. indica were identified from the literature and retrieved from the PubChem database. In silico screening was conducted to assess the inhibitory potential of these phytochemicals against three receptors (Schistosoma mansoni Thioredoxin glutathione reductase, dihydroorotate dehydrogenase, and Arginase) that may serve as therapeutic targets for schistosomiasis treatment. Molecular docking, ADMET prediction, ligand interaction, MMGBSA, and molecular dynamics simulation of the hit compounds were conducted using the Schrodinger molecular drug discovery suite. The results show that Andrographolide possesses a satisfactory pharmacokinetic profile, does not violate the Lipinski rule of five, binds with favourable affinity with the receptors, and interacts with key amino acids at the active site. Importantly, its interaction with dihydroorotate dehydrogenase, an enzyme responsible for the catalysis of the de novo pyrimidine nucleotide biosynthetic pathway rate-limiting step, shows a glide score and MMGBSA of -10.19 and -45.75 Kcal/mol, respectively. In addition, the MD simulation shows its stability at the active site of the receptor. Overall, this study revealed that Andrographolide from Azadirachta indica could serve as a potential lead compound for the development of an anti-schistosomal drug.


Subject(s)
Azadirachta , Dihydroorotate Dehydrogenase , Molecular Docking Simulation , Oxidoreductases Acting on CH-CH Group Donors , Schistosomiasis , Azadirachta/chemistry , Animals , Schistosomiasis/drug therapy , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Humans , Phytochemicals/pharmacology , Phytochemicals/chemistry , Molecular Dynamics Simulation , Schistosoma mansoni/drug effects , Schistosoma mansoni/enzymology , NADH, NADPH Oxidoreductases/antagonists & inhibitors , NADH, NADPH Oxidoreductases/metabolism , Plant Extracts/chemistry , Plant Extracts/pharmacology , Computer Simulation , Schistosomicides/pharmacology , Schistosomicides/chemistry , Schistosomicides/therapeutic use , Multienzyme Complexes/antagonists & inhibitors , Multienzyme Complexes/metabolism , Praziquantel/pharmacology , Praziquantel/chemistry , Praziquantel/therapeutic use
8.
ACS Infect Dis ; 10(5): 1664-1678, 2024 05 10.
Article in English | MEDLINE | ID: mdl-38686397

ABSTRACT

In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm Schistosoma mansoni and its target protease S. mansoni cathepsin B1 (SmCB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds' in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in S. mansoni newly transformed schistosomula (NTS), adult worms, and SmCB1 inhibition. The optimized compounds from both approaches ("phenotypic" vs "SmCB1" approach) demonstrated improved efficacy against S. mansoni NTS and adult worms, with 2h from the "SmCB1" approach emerging as the most potent compound. 2h displayed nanomolar inhibition of SmCB1 (Ki = 0.050 µM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound 2h toward S. mansoni adults (86% dead worms at 10 µM, 68% at 1 µM, 35% at 0.1 µM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.


Subject(s)
Cathepsin B , Schistosoma mansoni , Schistosoma mansoni/drug effects , Schistosoma mansoni/enzymology , Schistosoma mansoni/genetics , Animals , Cathepsin B/antagonists & inhibitors , Cathepsin B/metabolism , Schistosomiasis mansoni/drug therapy , Drug Design , Humans , Phenotype , Structure-Activity Relationship , Anthelmintics/pharmacology , Anthelmintics/chemistry , Helminth Proteins/antagonists & inhibitors
9.
Pestic Biochem Physiol ; 201: 105855, 2024 May.
Article in English | MEDLINE | ID: mdl-38685235

ABSTRACT

Biomphalaria spp. snails are freshwater gastropods that responsible for Schistosoma mansoni transmission. Schistosomiasis is a chronic illness that occurred in underdeveloped regions with poor sanitation. The aim of the present study is to evaluate the molluscicidal activity of benzylamine against B. alexandrina snails and it larvicidal effects on the free larval stages of S. mansoni. Results showed that benzylamine has molluscicidal activity against adult B. alexandrina snails after 24 h of exposure with median lethal concentration (LC50) 85.7 mg/L. The present results indicated the exposure of B. alexandrina snails to LC10 or LC25 of benzylamine resulted in significant decreases in the survival, fecundity (eggs/snail/week) and reproductive rates, acetylcholinesterase, albumin, protein, uric acid and creatinine concentrations, levels of Testosterone (T) and 17ß Estradiol (E), while alkaline phosphatase levels were significantly increased in comparison with control ones. The present results showed that the sub lethal concentration LC50 (85.7 mg/L) of benzylamine has miracidial and cercaricidal activities, where the Lethal Time (LT50) for miracidiae was 17.08 min while for cercariae was 30.6 min. Also, results showed that were decreased significantly after exposure to sub lethal concentrations compared with control. The present results showed that the expression level of NADH dehydrogenase subunit 1 (ND1) genes and cytochrome oxidase subunit I (COI) in B. alexandrina snails exposed to LC10 or LC25 concentrations benzylamine were significantly decreased compared to the control groups. Therefore, benzylamine could be used as effective molluscicide to control schistosomiasis.


Subject(s)
Biomphalaria , Larva , Schistosoma mansoni , Animals , Biomphalaria/drug effects , Schistosoma mansoni/drug effects , Larva/drug effects , Molluscacides/pharmacology
10.
Clin Infect Dis ; 78(Supplement_2): S126-S130, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38662698

ABSTRACT

BACKGROUND: The 2030 target for schistosomiasis is elimination as a public health problem (EPHP), achieved when the prevalence of heavy-intensity infection among school-aged children (SAC) reduces to <1%. To achieve this, the new World Health Organization guidelines recommend a broader target of population to include pre-SAC and adults. However, the probability of achieving EPHP should be expected to depend on patterns in repeated uptake of mass drug administration by individuals. METHODS: We employed 2 individual-based stochastic models to evaluate the impact of school-based and community-wide treatment and calculated the number of rounds required to achieve EPHP for Schistosoma mansoni by considering various levels of the population never treated (NT). We also considered 2 age-intensity profiles, corresponding to a low and high burden of infection in adults. RESULTS: The number of rounds needed to achieve this target depends on the baseline prevalence and the coverage used. For low- and moderate-transmission areas, EPHP can be achieved within 7 years if NT ≤10% and NT <5%, respectively. In high-transmission areas, community-wide treatment with NT <1% is required to achieve EPHP. CONCLUSIONS: The higher the intensity of transmission, and the lower the treatment coverage, the lower the acceptable value of NT becomes. Using more efficacious treatment regimens would permit NT values to be marginally higher. A balance between target treatment coverage and NT values may be an adequate treatment strategy depending on the epidemiological setting, but striving to increase coverage and/or minimize NT can shorten program duration.


Subject(s)
Disease Eradication , Schistosoma mansoni , Schistosomiasis mansoni , Humans , Schistosomiasis mansoni/epidemiology , Schistosomiasis mansoni/drug therapy , Schistosomiasis mansoni/prevention & control , Child , Animals , Adolescent , Schistosoma mansoni/drug effects , Adult , Prevalence , Mass Drug Administration , Public Health , Young Adult , Child, Preschool , Anthelmintics/therapeutic use , Anthelmintics/administration & dosage , Male , Female , Middle Aged
11.
Acta Trop ; 255: 107224, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38643822

ABSTRACT

Green silver nanoparticles (G-Ag NPs) have contributed to the development of ecological technologies with low environmental impact and safer for human health, as well as demonstrating potential for the control of vectors and intermediate hosts. However, knowledge about its toxicity in the early stages of gastropod development remains scarce. Therefore, the current study aimed to investigate the toxicity of G-Ag NPs synthesized from Croton urucurana leaf extracts in snail species Biomphalaria glabrata, which is an intermediate host for Schistosoma mansoni parasite. G-Ag NPs were synthesized using two types of plant extracts (aqueous and hydroethanolic) and characterized using multiple techniques. Bioassays focused on investigating G-Ag NPs and plant extracts were carried out with embryos and newly hatched snails, for 144 h and 96 h, respectively; toxicity was analyzed based on mortality, hatching, development inhibition, and morphological changes. Results have shown that both G-Ag NPs were more toxic to embryos and newly hatched snails than the investigated plant extracts. G-Ag NPs deriving from aqueous extract have higher molluscicidal activity than those deriving from hydroethanolic extract. Both G-Ag NPs induced mortality, hatching delay, development inhibition, and morphological changes (i.e., hydropic embryos), indicating their molluscicidal activities. Moreover, embryos were more sensitive to G-Ag NPs than newly hatched snails. Thus, the toxicity of G-Ag NPs to freshwater snails depends on the type of extracts and the snail's developmental stages. These findings can contribute to the development of green nanobiotechnologies applicable to control snails of medical importance.


Subject(s)
Biomphalaria , Croton , Metal Nanoparticles , Plant Extracts , Silver , Animals , Silver/toxicity , Biomphalaria/drug effects , Plant Extracts/toxicity , Plant Extracts/chemistry , Croton/chemistry , Metal Nanoparticles/toxicity , Metal Nanoparticles/chemistry , Fresh Water , Plant Leaves/chemistry , Molluscacides/toxicity , Schistosoma mansoni/drug effects , Green Chemistry Technology
12.
Chem Biodivers ; 21(5): e202400491, 2024 May.
Article in English | MEDLINE | ID: mdl-38470945

ABSTRACT

We have evaluated eight p-coumaric acid prenylated derivatives in vitro for their antileishmanial activity against Leishmania amazonensis promastigotes and their antischistosomal activity against Schistosoma mansoni adult worms. Compound 7 ((E)-3,4-diprenyl-4-isoprenyloxycinnamic alcohol) was the most active against L. amazonensis (IC50=45.92 µM) and S. mansoni (IC50=64.25 µM). Data indicated that the number of prenyl groups, the presence of hydroxyl at C9, and a single bond between C7 and C8 are important structural features for the antileishmanial activity of p-coumaric acid prenylated derivatives.


Subject(s)
Antiprotozoal Agents , Coumaric Acids , Leishmania , Parasitic Sensitivity Tests , Schistosoma mansoni , Animals , Schistosoma mansoni/drug effects , Coumaric Acids/pharmacology , Coumaric Acids/chemistry , Leishmania/drug effects , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Structure-Activity Relationship , Prenylation , Propionates/pharmacology , Propionates/chemistry , Molecular Structure , Schistosomicides/pharmacology , Schistosomicides/chemistry , Schistosomicides/chemical synthesis , Dose-Response Relationship, Drug
13.
J Biol Chem ; 300(1): 105528, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38043794

ABSTRACT

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.


Subject(s)
Anthelmintics , Clonazepam , Schistosomiasis mansoni , TRPM Cation Channels , Animals , Humans , Anthelmintics/pharmacology , Benzodiazepines/pharmacology , Benzodiazepinones/pharmacology , Clonazepam/analogs & derivatives , Clonazepam/pharmacology , Praziquantel/pharmacology , Schistosoma mansoni/drug effects , Schistosoma mansoni/metabolism , Schistosomiasis mansoni/drug therapy , TRPM Cation Channels/agonists
14.
BMC Res Notes ; 16(1): 266, 2023 Oct 10.
Article in English | MEDLINE | ID: mdl-37817269

ABSTRACT

OBJECTIVE: Galectins are sugar-binding proteins that participate in many biological processes, such as immunity, by regulating host immune cells and their direct interaction with pathogens. They are involved in mediating infection by Schistosoma mansoni, a parasitic trematode that causes schistosomiasis. However, their direct effects on schistosomes have not been investigated. RESULTS: We found that galectin-2 recognizes S. mansoni glycoconjugates and investigated whether galectin-1, 2, and 3 can directly affect S. mansoni in vitro. Adult S. mansoni were treated with recombinant galectin-1, 2, and 3 proteins or praziquantel, a positive control. Treatment with galectin-1, 2, and 3 had no significant effect on S. mansoni motility, and no other differences were observed under a stereoscopic microscope. Hence, galectin-1, 2, and 3 may have a little direct effect on S. mansoni. However, they might play a role in the infection in vivo via the modulation of the host immune response or secretory molecules from S. mansoni. To the best of our knowledge, this is the first study to investigate the direct effect of galectins on S. mansoni and helps in understanding the roles of galectins in S. mansoni infection in vivo.


Subject(s)
Galectins , Schistosoma mansoni , Schistosomiasis mansoni , Animals , Galectin 1/pharmacology , Galectins/pharmacology , Praziquantel/pharmacology , Schistosoma mansoni/drug effects , Schistosoma mansoni/physiology , Schistosomiasis mansoni/drug therapy
15.
ChemMedChem ; 18(3): e202200510, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36250286

ABSTRACT

Schistosoma mansoni HDAC8 is a reliable target to fight schistosomiasis, and several inhibitors have been reported in the literature up to now. Nevertheless, only a few displayed selectivity over the human deacetylases and some exhibited very low or no activity against parasite larvae and/or adult worms. We report here the in vitro enzyme and biological activity of a small library of HDAC inhibitors from our lab, in many cases exhibiting submicromolar/nanomolar potency against smHDAC8 and diverse degrees of selectivity over hHDAC1 and/or hHDAC6. Such compounds were tested against schistosomula, and a selection of them against the adult forms of S. mansoni, to detect their effect on viability. Some of them showed the highest viability reduction for the larval stage with IC50 values around 1 µM and/or displayed ∼40-50 % activity in adult worms at 10 µM, joined to moderate to no toxicity in human fibroblast MRC-5 cells.


Subject(s)
Histone Deacetylase Inhibitors , Histone Deacetylases , Schistosoma mansoni , Schistosomiasis , Adult , Animals , Humans , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylases/genetics , Larva/drug effects , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/genetics , Schistosoma mansoni/drug effects , Schistosoma mansoni/genetics , Schistosomiasis/drug therapy , Schistosomiasis/genetics
16.
Chem Biol Interact ; 368: 110191, 2022 Dec 01.
Article in English | MEDLINE | ID: mdl-36181831

ABSTRACT

Praziquantel (PZQ) is the only drug available for community-based control programs which aim to reduce the prevalence and morbidity associated with schistosomiasis. Here, we synthesized and evaluated the schistosomicidal, biochemical and cytotoxic activities of EF24, a synthetic curcumin analog, against different isolates of Schistosoma mansoni. EF24 elicited marked phenotypic alterations at 10 µM against schistosomula and 42-day-old adult worms of the Naval Medical Research Institute (NMRI) isolate. EF24 had 50% effective concentration (EC50) values of <10 µM against the Luis Evangelista (LE), Sergipe (SE), Belo Horizonte (BH) and Belo Horizonte less sensitive to PZQ (BH < PZQ) isolates of adult S. mansoni; however, the respective sensitivities of these isolates differed. Changes in the parasite included, vacuolization of the tegument and focal lysis of the interstitial tissue and muscle layers. Against 28-day-old juvenile worms (LE isolate), EF24 was about three times more potent than PZQ. After 6 h at 12.5 µM, EF24 increased reactive oxygen species (ROS) and the activity of the antioxidant enzyme, glutathione-S-transferase (GST), by 32 and 19% in female and male adult worms, respectively. By contrast, after 6 h at 12.5 µM glutathione reductase (GR) activity decreased by 43 and 30%, and glutathione peroxidase (GPx) activity decreased by 67 and 44% in females and males, respectively. EF24 was less cytotoxic to mammalian host cells than to S. mansoni, with selectivity indexes (SIs) of 1.8-3.4 and 2.7-7.5 for juvenile and adult worms, respectively. Given the current evidence for the in vitro schistosomicidal effect of EF24, the structure-activity relationship of additional analogs to identify new candidates for schistosomiasis treatment is warranted.


Subject(s)
Curcumin , Schistosoma mansoni , Schistosomicides , Animals , Female , Male , Antioxidants/metabolism , Curcumin/analogs & derivatives , Curcumin/pharmacology , Mammals , Praziquantel/pharmacology , Schistosoma mansoni/drug effects , Schistosomiasis/drug therapy , Schistosomicides/pharmacology , Glutathione Peroxidase/metabolism , Glutathione Transferase/metabolism , Reactive Oxygen Species/metabolism , Glutathione Reductase/metabolism
17.
Mar Drugs ; 20(2)2022 Jan 29.
Article in English | MEDLINE | ID: mdl-35200640

ABSTRACT

Schistosomiasis has been controlled for more than 40 years with a single drug, praziquantel, and only one molluscicide, niclosamide, raising concern of the possibility of the emergence of resistant strains. However, the molecular targets for both agents are thus far unknown. Consequently, the search for lead compounds from natural sources has been encouraged due to their diverse structure and function. Our search for natural compounds with potential use in schistosomiasis control led to the identification of an algal species, Laurencia dendroidea, whose extracts demonstrated significant activity toward both Schistosoma mansoni parasites and their intermediate host snails Biomphalaria glabrata. In the present study, three seaweed-derived halogenated sesquiterpenes, (-)-elatol, rogiolol, and obtusol are proposed as potential lead compounds for the development of anthelminthic drugs for the treatment of and pesticides for the environmental control of schistosomiasis. The three compounds were screened for their antischistosomal and molluscicidal activities. The screening revealed that rogiolol exhibits significant activity toward the survival of adult worms, and that all three compounds showed activity against S. mansoni cercariae and B. glabrata embryos. Biomonitored fractioning of L. dendroidea extracts indicated elatol as the most active compound toward cercariae larvae and snail embryos.


Subject(s)
Anthelmintics , Laurencia , Molluscacides , Sesquiterpenes , Animals , Anthelmintics/isolation & purification , Anthelmintics/pharmacology , Larva , Laurencia/chemistry , Molluscacides/isolation & purification , Molluscacides/pharmacology , Schistosoma mansoni/drug effects , Schistosomiasis/drug therapy , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Spiro Compounds/isolation & purification , Spiro Compounds/pharmacology
18.
Bioorg Med Chem Lett ; 59: 128546, 2022 03 01.
Article in English | MEDLINE | ID: mdl-35031451

ABSTRACT

We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro-γ-carboline substructures were required for high antischistosomal activity. Increasing polarity improved solubility and metabolic stability but decreased antischistosomal activity. We identified two compounds with IC50 values <5 µM against ex vivo Schistosoma mansoni.


Subject(s)
Carbolines/pharmacology , Schistosoma mansoni/drug effects , Sulfonamides/pharmacology , Animals , Carbolines/chemical synthesis , Carbolines/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
19.
Lancet Infect Dis ; 22(1): 136-149, 2022 01.
Article in English | MEDLINE | ID: mdl-34863336

ABSTRACT

BACKGROUND: Over the past 20 years, schistosomiasis control has been scaled up. Preventive chemotherapy with praziquantel is the main intervention. We aimed to assess the effect of preventive chemotherapy on schistosomiasis prevalence in sub-Saharan Africa, comparing 2000-10 with 2011-14 and 2015-19. METHODS: In this spatiotemporal modelling study, we analysed survey data from school-aged children (aged 5-14 years) in 44 countries across sub-Saharan Africa. The data were extracted from the Global Neglected Tropical Diseases database and augmented by 2018 and 2019 survey data obtained from disease control programmes. Bayesian geostatistical models were fitted to Schistosoma haematobium and Schistosoma mansoni survey data. The models included data on climatic predictors obtained from satellites and other open-source environmental databases and socioeconomic predictors obtained from various household surveys. Temporal changes in Schistosoma species prevalence were estimated by a categorical variable with values corresponding to the three time periods (2000-10, 2011-14, and 2015-19) during which preventive chemotherapy interventions were scaled up. FINDINGS: We identified 781 references with relevant geolocated schistosomiasis survey data for 2000-19. There were 19 166 unique survey locations for S haematobium and 23 861 for S mansoni, of which 77% (14 757 locations for S haematobium and 18 372 locations for S mansoni) corresponded to 2011-19. Schistosomiasis prevalence among school-aged children in sub-Saharan Africa decreased from 23·0% (95% Bayesian credible interval 22·1-24·1) in 2000-10 to 9·6% (9·1-10·2) in 2015-19, an overall reduction of 58·3%. The reduction of S haematobium was 67·9% (64·6-71·1) and that of S mansoni 53·6% (45·2-58·3) when comparing 2000-10 with 2015-19. INTERPRETATION: Our model-based estimates suggest that schistosomiasis prevalence in sub-Saharan Africa has decreased considerably, most likely explained by the scale-up of preventive chemotherapy. There is a need to consolidate gains in the control of schistosomiasis by means of preventive chemotherapy, coupled with other interventions to interrupt disease transmission. FUNDING: European Research Council and WHO.


Subject(s)
Anthelmintics/therapeutic use , Praziquantel/therapeutic use , Schistosoma haematobium/drug effects , Schistosoma mansoni/drug effects , Schistosomiasis/drug therapy , Spatio-Temporal Analysis , Adolescent , Africa South of the Sahara/epidemiology , Animals , Chemoprevention , Child , Child, Preschool , Cross-Sectional Studies , Databases, Factual , Humans , Praziquantel/administration & dosage , Prevalence , Schistosomiasis/classification , Schistosomiasis/epidemiology , Schools
20.
Molecules ; 26(24)2021 Dec 10.
Article in English | MEDLINE | ID: mdl-34946555

ABSTRACT

Leishmaniasis and schistosomiasis are neglected tropical diseases (NTDs) infecting the world's poorest populations. Effectiveness of the current antileishmanial and antischistosomal therapies are significantly declining, which calls for an urgent need of new effective and safe drugs. In Ethiopia fresh leaves of Ranunculus multifidus Forsk. are traditionally used for the treatment of various ailments including leishmaniasis and eradication of intestinal worms. In the current study, anemonin isolated from the fresh leaves of R. multifidus was assessed for its in vitro antileishmanial and antischistosomal activities. Anemonin was isolated from the hydro-distilled extract of the leaves of R. multifidus. Antileishmanial activity was assessed on clinical isolates of the promastigote and amastigote forms of Leishmania aethiopica and L. donovani clinical isolates. Resazurin reduction assay was used to determine antipromastigote activity, while macrophages were employed for antiamastigote and cytotoxicity assays. Antischistosomal assays were performed against adult Schistosoma mansoni and newly transformed schistosomules (NTS). Anemonin displayed significant antileishmanial activity with IC50 values of 1.33 nM and 1.58 nM against promastigotes and 1.24 nM and 1.91 nM against amastigotes of L. aethiopica and L. donovani, respectively. It also showed moderate activity against adult S. mansoni and NTS (49% activity against adult S. mansoni at 10 µM and 41% activity against NTS at 1 µM). The results obtained in this investigation indicate that anemonin has the potential to be used as a template for designing novel antileishmanial and antischistosomal pharmacophores.


Subject(s)
Antiprotozoal Agents/pharmacology , Furans/pharmacology , Leishmania/drug effects , Plant Extracts/pharmacology , Ranunculus/chemistry , Schistosoma mansoni/drug effects , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/isolation & purification , Furans/chemistry , Furans/isolation & purification , Parasitic Sensitivity Tests , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Leaves/chemistry
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