In silico repositioning of approved drugs against Schistosoma mansoni energy metabolism targets

Calixto, Nicole Melo; Santos, Daniela Braz dos; Bezerra, José Clecildo Barreto; Silva, Lourival de Almeida

doi:10.1371/journal.pone.0203340

Cited by 7 publications

(6 citation statements)

References 48 publications

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“…To fast track such investigations, an extensive collection of putative S. mansoni drug candidates is currently available within the TDR Targets database [70]. Alongside this resource, multiple reports have recently described how genome sequencing outputs can be effectively leveraged by both cheminformatics and functional genomics for characterising next-generation schistosome drug targets and chemotherapeutics [66,[71][72][73][74][75][76]. Complementary evidence is provided here to support an essential role for SmNAGAL in the regulation of worm movement and reproductive processes.…”

Section: Discussionmentioning

confidence: 83%

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

Hulme

Geyer

Forde-Thomas

et al. 2021

Preprint

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α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni’s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Pharmacological inhibition of SmNAGAL may lead to the development of a novel anthelmintic class of compounds.

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Section: Discussionmentioning

confidence: 83%

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

Hulme

Geyer

Forde-Thomas

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…mansoni drug candidates is currently available within the TDR Targets database [ 84 ]. Alongside this resource, multiple reports have recently described how genome sequencing outputs can be effectively leveraged by both cheminformatics and functional genomics for characterising next-generation schistosome drug targets and chemotherapeutics [ 74 , 85 – 90 ]. Complementary evidence is provided here to support an essential role for SmNAGAL in the regulation of worm movement and reproductive processes.…”

Section: Discussionmentioning

confidence: 99%

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

et al. 2022

View full text Add to dashboard Cite

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni’s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.

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“…Foram encontrados e analisados 44 artigos científicos quanto à epidemiologia da esquistossomose mansônica, publicados em 14 periódicos diferentes. VITORINO et al, 2012;CALIXTO et al, 2018). Apesar de haver pesquisas em outras regiões, como no Nordeste (Piauí, Bahia, Maranhão), as produções dessas outras partes do país ainda são insuficientes, se fazendo necessário o incentivo a pesquisas tanto em áreas endêmicas como em não endêmicas.…”

Section: Epidemiologia Da Esquistossomose Mansoniunclassified

Literatura científica brasileira sobre a pesquisa da esquistossomose mansônica: acervos, vieses e direções futuras

Leite

Miranda

Silva

et al. 2022

CONJ

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O presente estudo de cienciometria objetivou conhecer a produção científica brasileira sobre a esquistossomose ao longo de vinte anos, procurando conhecer as revistas que mais publicaram sobre o assunto, as instiuiçoes e os pesquisadores envolvidos. Foram encontradas 991 publicações, sendo analisadas 214 pois atendiam aos critérios de inclusão. Nos primeiros dez anos, se destacaram as formas clínicas da parasitose e, posteriormente, assuntos como a transmissão, epidemiologia, controle e tratamento passaram a ser prioridades. Os periódicos que mais publicaram artigos sobre a temática foram, as Memórias do Instituto Oswaldo Cruz e a Revista da Sociedade Brasileira de Medicina Tropical. Diversos autores destacaram-se, além das instituições Universidade Federal de Minas Gerais, Centro Pesquisa René-Rachou e o Centro de Pesquisa Aggeu Magalhães (FIOCRUZ). Constatou-se que as pesquisas brasileiras ainda podem ser consideradas escassas e centralizadas, em especial quando se atesta a existência de áreas históricas endêmicas de esquistossomose, sua expansão para outras regiões e a constante carência de saneamento básico em extensas áreas do país.

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In silico repositioning of approved drugs against Schistosoma mansoni energy metabolism targets

Cited by 7 publications

References 48 publications

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

Literatura científica brasileira sobre a pesquisa da esquistossomose mansônica: acervos, vieses e direções futuras

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