Abstract:
:Neglected tropical diseases are of growing worldwide concern and schistosomiasis, caused by parasitic flatworms, continues to be a major threat with more than 200 million people requiring preventive treatment. As praziquantel (PZQ) remains the treatment of choice, an urgent need for alternative treatments motivates research to identify new lead compounds that would complement PZQ by filling the therapeutic gaps associated with this treatment. Because impairing parasite neurotransmission remains a core strategy for control of parasitic helminths, we screened a library of 708 compounds with validated biological activity in humans on the blood fluke Schistosoma mansoni, measuring their effect on the motility on schistosomulae and adult worms. The primary phenotypic screen performed on schistosomulae identified 70 compounds that induced changes in viability and/or motility. Screening different concentrations and incubation times identified molecules with fast onset of activity on both life stages at low concentration (1 μM). To complement this study, similar assays were performed with chemical analogs of the cholinomimetic drug arecoline and the calcilytic molecule NPS-2143, two compounds that rapidly inhibited schistosome motility; 17 arecoline and 302 NPS-2143 analogs were tested to enlarge the pool of schistosomicidal molecules. Finally, validated hit compounds were tested on three functionally-validated neuroregulatory S. mansoni G-protein coupled receptors (GPCRs): Sm5HTR (serotonin-sensitive), SmGPR2 (histamine) and SmD2 (dopamine), revealing NPS-2143 and analogs as potent inhibitors of dopamine/epinine responses on both human and S. mansoni GPCRs. This study highlights the potential for repurposing known human therapeutic agents for potential schistosomicidal effects and expands the list of hits for further progression.
journal_name
Int J Parasitol Drugs Drug Resistauthors
Duguet TB,Glebov A,Hussain A,Kulkarni S,Mochalkin I,Geary TG,Rashid M,Spangenberg T,Ribeiro Pdoi
10.1016/j.ijpddr.2020.05.002subject
Has Abstractpub_date
2020-08-01 00:00:00pages
73-88issn
2211-3207pii
S2211-3207(20)30012-9journal_volume
13pub_type
杂志文章abstract::Schistosomiasis is a neglected tropical disease caused by blood-dwelling flukes of the genus Schistosoma. While the disease may affect as many as 249 million people, treatment largely relies on a single drug, praziquantel. The near exclusive use of this drug for such a prevalent disease has led to concerns regarding t...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2014.09.006
更新日期:2014-09-26 00:00:00
abstract::Toxicity and poor adherence to treatment that favors the generation of resistance in the Leishmania parasites highlight the need to develop better alternatives. Here, we evaluated the in vitro effectiveness of hydrazone derived from chromanes 2-(2,3-dihydro-4H-1-benzothiopyran-4-ylidene) hydrazide (TC1) and 2-(2,3-dih...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.06.004
更新日期:2020-08-01 00:00:00
abstract::Drug resistance is a problem wherever livestock are raised under intensive conditions and drugs are used to combat parasitic infections. This is particularly true for the anticoccidial agents used for the prevention of coccidiosis caused by protozoa of the apicomplexan genus Eimeria in poultry. Resistance has been doc...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2014.10.002
更新日期:2014-10-25 00:00:00
abstract::Anthelmintic resistance (AR) to Fasciola hepatica is emerging worldwide. Recently, AR to the adulticide compound albendazole (ABZ) was shown in Argentina and Spain. In Sweden, ABZ treatment failure against F. hepatica was first reported in sheep in 2012. The present study tested the efficacy of ABZ and triclabendazole...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2016.06.004
更新日期:2016-12-01 00:00:00
abstract::Leishmania panamensis is a relevant causative agent of tegumentary leishmaniasis in several Latin American countries. Available antileishmanial drugs have several limitations including relatively high toxicity, difficult administration, high production costs and the emergence of resistance in circulating strains. Ther...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.08.002
更新日期:2020-12-01 00:00:00
abstract::The high level of resistance to the macrocyclic lactones has encouraged the search for strategies to optimize their potential as antiparasitic agents. There is a need for pharmaco-parasitological studies addressing the kinetic-dynamic differences between various macrocyclic lactones under standardized in vivo conditio...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2012.11.001
更新日期:2012-12-03 00:00:00
abstract::The four components present in the trypanocidal treatment Samorin, the commercially available formulation of isometamidium, were separated and purified by column chromatography. These compounds as well as the Samorin mixture and the other phenanthridine trypanocide, homidium, were tested on Trypanosoma congolense and ...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2019.01.003
更新日期:2019-04-01 00:00:00
abstract:OBJECTIVES:This study evaluated the implications of clinically acquired miltefosine resistance (MIL-R) by assessing virulence in mice and sand flies to reveal the potential of MIL-R strains to circulate. METHODS:Experimental infections with the MIL-R clinical Leishmania infantum isolate MHOM/FR/2005/LEM5159, having a ...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.04.004
更新日期:2020-08-01 00:00:00
abstract::Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2016.12.005
更新日期:2017-04-01 00:00:00
abstract::Toxoplasma gondii, an obligate intracellular protozoan, is the causative agent of toxoplasmosis, which can cause serious public health problems. The current drugs used to treat toxoplasmosis have many limitations. This study evaluated the anti-T. gondii activity and potential mechanism of Licochalcone A (Lico A) in vi...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2018.02.006
更新日期:2018-08-01 00:00:00
abstract::The effect of Camellia sinensis (green tea) on the growth of Acanthamoeba castellanii trophozoites was examined using a microplate based-Sulforhodamine B (SRB) assay. C. sinensis hot and cold brews at 75% and 100% concentrations significantly inhibited the growth of trophozoites. We also examined the structural altera...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.05.001
更新日期:2020-08-01 00:00:00
abstract::Knockdown-resistance (kdr) against pyrethroids in bed bugs (Cimex lectularis) is associated with the presence of several point mutations in the voltage-sensitive sodium channel α-subunit gene and/or an increased metabolic detoxification by cytochrome P450 monooxygenases (CYPs). In the present study, pyrosequencing ass...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.11.003
更新日期:2020-12-01 00:00:00
abstract::We examined faecal egg count reduction tests (FECRTs) conducted with hookworm-infected humans in Ghana in 2007 (study 1) and 2010 (study 2) in order to explore aspects of the test analysis. Some subjects showed increased FEC following drug treatment. This occurred mostly in <150 epg pre-treatment FEC subjects. We soug...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2014.01.001
更新日期:2014-01-31 00:00:00
abstract::It is recognized that the clinical efficacy of single dose benzimidazoles (BZs) against the nematode, Trichuris suis of pigs and the closely related Trichuris trichiura in humans is only poor to moderate. Recent in vitro studies have indicated that a low uptake of fenbendazole (FBZ) in T. suis may be responsible for i...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2014.03.003
更新日期:2014-04-08 00:00:00
abstract::The need for new antimalarials is persistent due to the emergence of drug resistant parasites. Here we aim to identify new drug targets in Plasmodium falciparum by phylogenomics among the Plasmodium spp. and comparative genomics to Homo sapiens. The proposed target discovery pipeline is largely independent of experime...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2012.07.002
更新日期:2012-07-17 00:00:00
abstract::Millions of people are treated with anthelmintics to control soil-transmitted helminth infections; yet, drug distribution in the plasma and gastrointestinal tract compartments and the pathway of drug uptake into gastrointestinal nematodes responsible for the pharmacological effect are unknown. We assessed the distribu...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2017.03.005
更新日期:2017-08-01 00:00:00
abstract::Clinical studies suggest that outcomes for hospitalised malaria patients can be improved by managed hypothermia during treatment. We examined the impact of short pulses of low temperature on ring-stage susceptibility of Plasmodium falciparum to artemisinin in vitro. The usually artemisinin-sensitive clone 3D7 exhibite...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2018.12.003
更新日期:2019-04-01 00:00:00
abstract::Dirofilaria immitis is a filarial nematode causing infection and heartworm disease in dogs and other canids, cats, and occasionally in humans. Prevention with macrocyclic lactones (ML) is recommended during the mosquito transmission season. Recently, ML resistance has been reported. ABC-B transporter genes are thought...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2016.04.001
更新日期:2016-08-01 00:00:00
abstract::The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2018.02.002
更新日期:2018-04-01 00:00:00
abstract::Anthelmintic resistant gastrointestinal helminths have become a major cause of poor health in sheep and goats. Sensitive and specific molecular markers are needed to monitor the genotypic frequency of resistance in field parasite populations. Gastrointestinal nematode resistance to benzimidazole is caused by a mutatio...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2019.08.003
更新日期:2019-08-01 00:00:00
abstract::Cryptosporidium and Toxoplasma are parasites that have caused problems worldwide. Cryptosporidium causes severe watery diarrhoea and may be fatal in immunocompromised patients and in infants. Nitazoxanide is the only agent currently approved by the FDA, but its efficacy is limited. Toxoplasmosis is also a problem in t...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.10.004
更新日期:2020-12-01 00:00:00
abstract::Haemonchus contortus is a critical parasite of goats and sheep. Infection by this blood-feeding gastrointestinal nematode (GIN) parasite has significant health consequences, especially in lambs and kids. The parasite has developed resistance to virtually all known classes of small molecule anthelmintics used to treat ...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.11.004
更新日期:2020-12-01 00:00:00
abstract::Soil-transmitted helminths cause more than 1 billion human infections globally, mostly in the poorest regions of the world. Control relies essentially on a limited panel of four drugs, and drug resistance might be inescapable. Nitazoxanide, an anti-infective drug, has been shown to exert anthelmintic activity in human...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2012.02.004
更新日期:2012-03-10 00:00:00
abstract::Isometamidium Chloride (ISM) is one of the principal drugs used to counteract Trypanosoma congolense infection in livestock, both as a prophylactic as well as a curative treatment. However, numerous cases of ISM resistance have been reported in different African regions, representing a significant constraint in the ba...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2017.10.002
更新日期:2017-12-01 00:00:00
abstract::Infections with parasitic nematodes are among the most significant of the neglected tropical diseases affecting about a billion people living mainly in tropical regions with low economic activity. The most effective current strategy to control nematode infections involves large scale treatment programs with anthelmint...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2019.04.001
更新日期:2019-08-01 00:00:00
abstract::Nematode cys-loop ligand-gated ion channels (LGICs) have been shown to be attractive targets for the development of novel anti-parasitic drugs. The ACC-1 family of receptors are a unique group of acetylcholine-gated chloride channels present only in invertebrates, and sequence analysis suggests that they contain a nov...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2018.09.004
更新日期:2018-12-01 00:00:00
abstract::The control of parasitic nematodes impacting animal health relies on the use of broad spectrum anthelmintics. However, intensive use of these drugs has led to the selection of resistant parasites in livestock industry. In that respect, there is currently an urgent need for novel compounds able to control resistant par...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2018.11.003
更新日期:2018-12-01 00:00:00
abstract::Anthelmintic resistance has emerged as an important problem in animal industries. Understanding resistance mechanisms, especially against macrocyclic lactones (MLs), is the first step in developing better diagnostic tools. Effects of several MLs including ivermectins and milbemycins were tested using two well establis...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2013.04.002
更新日期:2013-05-24 00:00:00
abstract::Toxoplasma gondii and Cryptosporidium parvum are protozoan parasites that are highly prevalent and opportunistically infect humans worldwide, but for which completely effective and safe medications are lacking. Herein, we synthesized a series of novel small molecules bearing the diacyl urea scaffold and related struct...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2020.08.006
更新日期:2020-12-01 00:00:00
abstract::The Coenzyme A (CoA), as a cofactor involved in >100 metabolic reactions, is essential to the basic biochemistry of life. Here, we investigated the CoA biosynthetic pathway of Entamoeba histolytica (E. histolytica), an enteric protozoan parasite responsible for human amebiasis. We identified four key enzymes involved ...
journal_title:International journal for parasitology. Drugs and drug resistance
pub_type: 杂志文章
doi:10.1016/j.ijpddr.2018.02.004
更新日期:2018-04-01 00:00:00