Genetic analysis of praziquantel response in schistosome parasites implicates a Transient Receptor Potential channel

Clec’h, Winka Le; Chevalier, Frédéric D.; Mattos, Ana Carolina Alves de; Strickland, Amanda; Diaz, Robbie; McDew-White, Marina; Rohr, Claudia; Kinung’hi, Safari; Allan, Fiona; Webster, Bonnie L.; Webster, Joanne P.; Emery, Aidan; David, Rollinson; Djirmay, Amadou Garba; Mashikhi, Khalid Al; Yafae, Salem Al; Idris, Mohamed A.; Moné, Hélène; Mouahid, Gabriel; LoVerde, Philip T.; Marchant, Jonathan S.; Anderson, Timothy J.

doi:10.1101/2021.06.09.447779

Cited by 5 publications

(1 citation statement)

References 80 publications

(46 reference statements)

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“…A recent metaanalysis of PZQ efficacy over four decades indicates cure rates between 57-88% (2), but there is the concern that resistance may emerge with repeated rounds of mass drug administration (3). Parasite resistance can be selected in the laboratory (4)(5)(6), and there are numerous reports of treatment failure in the field (7,8). An alternative antischistosomal drug would be of obvious use in the event of either PZQ treatment failure or resistance.…”

Section: Introductionmentioning

confidence: 99%

Development of non-sedating antischistosomal benzodiazepines

Mian,

Sharmin,

Mondal

et al. 2024

Preprint

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The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970's. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index, and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

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Section: Introductionmentioning

confidence: 99%

Development of non-sedating antischistosomal benzodiazepines

Mian,

Sharmin,

Mondal

et al. 2024

Preprint

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Whole-genome sequencing of Schistosoma mansoni reveals extensive diversity with limited selection despite mass drug administration

et al. 2021

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Control and elimination of the parasitic disease schistosomiasis relies on mass administration of praziquantel. Whilst these programmes reduce infection prevalence and intensity, their impact on parasite transmission and evolution is poorly understood. Here we examine the genomic impact of repeated mass drug administration on Schistosoma mansoni populations with documented reduced praziquantel efficacy. We sequenced whole-genomes of 198 S. mansoni larvae from 34 Ugandan children from regions with contrasting praziquantel exposure. Parasites infecting children from Lake Victoria, a transmission hotspot, form a diverse panmictic population. A single round of treatment did not reduce this diversity with no apparent population contraction caused by long-term praziquantel use. We find evidence of positive selection acting on members of gene families previously implicated in praziquantel action, but detect no high frequency functionally impactful variants. As efforts to eliminate schistosomiasis intensify, our study provides a foundation for genomic surveillance of this major human parasite.

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Assembled chromosomes of the blood fluke Schistosoma mansoni provide insight into the evolution of its ZW sex-determination system

Buddenborg

Tracey

Berger

et al. 2021

Preprint

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Background: Schistosoma mansoni is a flatworm that causes a neglected tropical disease affecting millions worldwide. Most flatworms are hermaphrodites but schistosomes have genotypically determined male (ZZ) and female (ZW) sexes. Sex is essential for pathology and transmission, however, the molecular determinants of sex remain unknown and is limited by poorly resolved sex chromosomes in previous genome assemblies. Results: We assembled the 391.4 Mb S. mansoni genome into individual, single-scaffold chromosomes, including Z and W. Manual curation resulted in a vastly improved gene annotation, resolved gene and repeat arrays, trans-splicing, and almost all UTRs. The sex chromosomes each comprise pseudoautosomal regions and single sex-specific regions. The Z-specific region contains 932 genes, but on W all but 29 of these genes have been lost and the presence of five pseudogenes indicates that degeneration of W is ongoing. Synteny analysis reveals an ancient chromosomal fusion corresponding to the oldest part of Z, where only a single gene-encoding the large subunit of pre-mRNA splicing factor U2AF has retained an intact copy on W. The sex-specific copies of U2AF have divergent N-termini and show sex-biased gene expression. Conclusion: Our assembly with fully resolved chromosomes provides evidence of an evolutionary path taken to create the Z and W sex chromosomes of schistosomes. Sex-linked divergence of the single U2AF gene, which has been present in the sex-specific regions longer than any other extant gene with distinct male and female specific copies and expression, may have been a pivotal step in the evolution of gonorchorism and genotypic sex determination of schistosomes.

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Genetic analysis of praziquantel response in schistosome parasites implicates a Transient Receptor Potential channel

Cited by 5 publications

References 80 publications

Development of non-sedating antischistosomal benzodiazepines

Development of non-sedating antischistosomal benzodiazepines

Whole-genome sequencing of Schistosoma mansoni reveals extensive diversity with limited selection despite mass drug administration

Assembled chromosomes of the blood fluke Schistosoma mansoni provide insight into the evolution of its ZW sex-determination system

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