Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

Stofberg, Melissa Louise; Caillet, Celine; Villiers, Marianne de; Zininga, Tawanda

doi:10.3390/cells10112849

Cited by 10 publications

(5 citation statements)

References 196 publications

(339 reference statements)

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Section: Introductionmentioning

confidence: 99%

“…1 Although there are clinically approved antimalarial agents in use, drug resistance has spread quickly and widely, and the limited availability of antimalarials has led many researchers to seek new antimalarials. [2][3][4] In Plasmodium, thiamine 1 (Fig. 1) is converted into its active form, thiamine pyrophosphate (TPP) 2, by the enzyme thiamine pyrophosphokinase (TPK).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity

Chan

Fathoni

et al. 2022

RSC Med. Chem.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity

Chan

Fathoni

et al. 2022

RSC Med. Chem.

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“…The aim of presenting these novel insights is to provide a valuable framework for future research investigating the importance of HSPs to schistosome growth, development, maturation and survival. In recent years, there has been an increased focus on HSPs in the field of disease research, with HSPs considered promising drug targets for infectious diseases and non-communicable diseases like cancer [ 65 – 68 ]. Several attributes of HSPs make them potential drug targets for the treatment of human schistosomiasis.…”

Section: Discussionmentioning

confidence: 99%

Molecular insights into the heat shock proteins of the human parasitic blood fluke Schistosoma mansoni

2022

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Background Heat shock proteins (HSPs) are evolutionarily conserved proteins, produced by cells in response to hostile environmental conditions, that are vital to organism homeostasis. Here, we undertook the first detailed molecular bioinformatic analysis of these important proteins and mapped their tissue expression in the human parasitic blood fluke, Schistosoma mansoni, one of the causative agents of the neglected tropical disease human schistosomiasis. Methods Using bioinformatic tools we classified and phylogenetically analysed HSP family members in schistosomes, and performed transcriptomic, phosphoproteomic, and interactomic analysis of the S. mansoni HSPs. In addition, S. mansoni HSP protein expression was mapped in intact parasites using immunofluorescence. Results Fifty-five HSPs were identified in S. mansoni across five HSP families; high conservation of HSP sequences were apparent across S. mansoni, Schistosoma haematobium and Schistosoma japonicum, with S. haematobium HSPs showing greater similarity to S. mansoni than those of S. japonicum. For S. mansoni, differential HSP gene expression was evident across the various parasite life stages, supporting varying roles for the HSPs in the different stages, and suggesting that they might confer some degree of protection during life stage transitions. Protein expression patterns of HSPs were visualised in intact S. mansoni cercariae, 3 h and 24 h somules, and adult male and female worms, revealing HSPs in the tegument, cephalic ganglia, tubercles, testes, ovaries as well as other important organs. Analysis of putative HSP protein-protein associations highlighted proteins that are involved in transcription, modification, stability, and ubiquitination; functional enrichment analysis revealed functions for HSP networks in S. mansoni including protein export for HSP 40/70, and FOXO/mTOR signalling for HSP90 networks. Finally, a total of 76 phosphorylation sites were discovered within 17 of the 55 HSPs, with 30 phosphorylation sites being conserved with those of human HSPs, highlighting their likely core functional significance. Conclusions This analysis highlights the fascinating biology of S. mansoni HSPs and their likely importance to schistosome function, offering a valuable and novel framework for future physiological investigations into the roles of HSPs in schistosomes, particularly in the context of survival in the host and with the aim of developing novel anti-schistosome therapeutics.

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“…Unsatisfactory leishmaniasis treatment encourages researchers to investigate more modern options, which now target the parasite's functioning proteins or molecules. The heat shock protein 90 (Hsp90) is believed to be a commendable drug target against parasitic diseases (Debnath et al, 2014), (Stofberg et al, 2021), (O. Angel et al, 2013), (Silva et al, 2013), (De Andrade et al, 1992.…”

Section: Exploration Of the Potential Modulator To Modulate Autophagy...mentioning

confidence: 99%

Systems biology of autophagy in leishmanial infection and its diverse role in precision medicine

Guhe

Ingale

Tambekar

et al. 2023

Front. Mol. Biosci.

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Autophagy is a contentious issue in leishmaniasis and is emerging as a promising therapeutic regimen. Published research on the impact of autophagic regulation on Leishmania survival is inconclusive, despite numerous pieces of evidence that Leishmania spp. triggers autophagy in a variety of cell types. The mechanistic approach is poorly understood in the Leishmania parasite as autophagy is significant in both Leishmania and the host. Herein, this review discusses the autophagy proteins that are being investigated as potential therapeutic targets, the connection between autophagy and lipid metabolism, and microRNAs that regulate autophagy and lipid metabolism. It also highlights the use of systems biology to develop novel autophagy-dependent therapeutics for leishmaniasis by utilizing artificial intelligence (AI), machine learning (ML), mathematical modeling, network analysis, and other computational methods. Additionally, we have shown many databases for autophagy and metabolism in Leishmania parasites that suggest potential therapeutic targets for intricate signaling in the autophagy system. In a nutshell, the detailed understanding of the dynamics of autophagy in conjunction with lipids and miRNAs unfolds larger dimensions for future research.

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Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

Cited by 10 publications

References 196 publications

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity

Molecular insights into the heat shock proteins of the human parasitic blood fluke Schistosoma mansoni

Systems biology of autophagy in leishmanial infection and its diverse role in precision medicine

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