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      The discovery of a novel series of compounds with single-dose efficacy against juvenile and adult Schistosoma species

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          Abstract

          Treatment and control of schistosomiasis depends on a single drug, praziquantel, but this is not ideal for several reasons including lack of potency against the juvenile stage of the parasite, dose size, and risk of resistance. We have optimised the properties of a series of compounds we discovered through high throughput screening and have designed candidates for clinical development. The best compounds demonstrate clearance of both juvenile and adult S. mansoni worms in a mouse model of infection from a single oral dose of < 10 mg/kg. Several compounds in the series are predicted to treat schistosomiasis in humans across a range of species with a single oral dose of less than 5 mg/kg.

          Author summary

          Schistosomiasis (also known as Bilharzia) is a severe disease with WHO estimates suggesting that more than 229 million people require preventative treatment. It is caused by parasitic worms which infect through the skin and, when mature, pair up in different parts of the body according to species, and produce eggs leading to significant adverse health impacts including death. Treatment is reliant on one drug, praziquantel, which is effective against adult worms, but has some disadvantages. Praziquantel is not effective against juvenile worms and is therefore unable to prevent the disease. Also, a large dose is required, and furthermore, reliance on one drug risks the development of drug resistance. This research describes the discovery of a new series of potent compounds, unrelated to praziquantel, which kill both the adult and juvenile parasitic worms in vitro, and in mice, following a low single oral dose. Predictions suggest that several of the compounds should be capable of curing infection in people with a single oral dose approximately 10-fold smaller than praziquantel.

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          Most cited references26

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          Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays

          A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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            DrugBank 5.0: a major update to the DrugBank database for 2018

            Abstract DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year’s update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education.
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              Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment.

              The efficacy of praziquantel against a Puerto Rican strain of Schistosoma mansoni was assessed using both in vivo and in vitro approach. The drug effective dose (50%) in the infected mouse model was about 30 times higher when determined against 28-day-old infections than against 7-week-old parasites. Single-sex female infections were also largely refractory to treatment and single-sex male infections moderately refractory, in comparison with bisexual infections. The in vitro approach consisted of overnight exposure of parasite cultures to various drug concentrations, followed by several days of culture in drug-free medium. In vitro results confirmed in vivo data and allowed for the observation of schistosome morphological phenomena after praziquantel exposure. Early worm contraction was observed in all cases, even after exposure to sub-lethal concentrations of praziquantel or upon exposure of the largely refractory 28-day-old schistosomes. In these instances, however, worms resumed movements and normal shape upon drug removal and were able to survive. The inference of these observations on the clinical use of praziquantel and on its mechanism of action is discussed.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                19 July 2021
                July 2021
                : 15
                : 7
                : e0009490
                Affiliations
                [1 ] Salvensis, Sandwich, Kent, United Kingdom
                [2 ] Department for Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
                University of Pennsylvania, UNITED STATES
                Author notes

                I have read the journal’s policy and the authors of this manuscript have the following competing interests: Since the project work was completed JMFG has taken on a small consultancy with Merck KGaA who are now the assignee of the patents covering this work.

                Author information
                https://orcid.org/0000-0002-9322-1181
                https://orcid.org/0000-0001-5579-8708
                https://orcid.org/0000-0002-0581-9387
                https://orcid.org/0000-0003-0761-7348
                https://orcid.org/0000-0003-1504-2660
                Article
                PNTD-D-21-00141
                10.1371/journal.pntd.0009490
                8321398
                34280206
                cdde086e-a846-481a-bbf3-612b134c6be5
                © 2021 Gardner et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 February 2021
                : 23 May 2021
                Page count
                Figures: 10, Tables: 4, Pages: 21
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MR/ K025430/1
                Award Recipient :
                Work was funded by the Medical Research Council, United Kingdom, grant award number MR/ K025430/1 made to QB ( https://mrc.ukri.org/). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmaceutics
                Dose Prediction Methods
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Invertebrates
                Helminths
                Schistosoma
                Schistosoma Mansoni
                Biology and Life Sciences
                Zoology
                Animals
                Invertebrates
                Helminths
                Schistosoma
                Schistosoma Mansoni
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Mouse Models
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Biochemistry
                Lipids
                Oils
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Hepatocytes
                Biology and Life Sciences
                Anatomy
                Liver
                Hepatocytes
                Medicine and Health Sciences
                Anatomy
                Liver
                Hepatocytes
                Research and Analysis Methods
                Chemical Synthesis
                Biology and Life Sciences
                Biochemistry
                Proteins
                Plasma Proteins
                Custom metadata
                vor-update-to-uncorrected-proof
                2021-07-29
                The vast majority of the data is available within the manuscript and supporting information. Data is also available at https://chembl.gitbook.io/chembl-ntd/downloads/deposited-set-25-schistosoma-dataset-1st-july-2021 and https://chembl.gitbook.io/chembl-ntd/downloads/deposited-set-25-schistosoma-dataset-1st-july-2021

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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