Target acquired: transcriptional regulators as drug targets for protozoan parasites

Walters, Heather A.; Temesvari, Lesly A.

doi:10.1016/j.ijpara.2020.12.007

Cited by 4 publications

(4 citation statements)

References 78 publications

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“…Although transcription factors have been considered an undruggable target, recent evidence points to them as promising therapeutic targets for the treatment of various diseases such as cancer, and their potential use in the treatment of parasitic diseases has even been suggested [ 19 , 22 ]. Even though the TBP is an essential element for transcription and almost its entire surface interacts with other transcription factors or DNA, the use of the TBP as a therapeutic target has been under research [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is worth mentioning that recent studies conducted by Santiago et al [ 15 ] identify several regions of the convex part of the TBP protein in protists, such as E. histolytica and P. falciparum , as susceptible therapeutic targets due to the morphological and amino acid sequence differences they exhibit. It has been postulated that inhibiting protein–protein or protein–DNA interactions using small molecules could cause a disruption in transcription that is detrimental to the parasite [ 19 , 22 ]. Therefore, TBPs with sufficient sequence divergence are susceptible to being used as a therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, transcription factors have been considered a promising target for treating parasitic diseases. This is mainly attributed to the differences in protein sequences regarding higher eukaryotes and the reported low mutation rate [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…A molecule with the necessary affinity for the NC2 motif could similarly hinder the formation of the preinitiation complex by occluding TFIIA and TFIIB, to the detriment of the parasite. These types of inhibition strategies are further explained by Lambert et al, 2018 and Walters et al, 2021, with perspectives for treating cancer and parasitic diseases caused by protists [ 19 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents

Gaona-López,

Méndez-Álvarez,

Moreno-Rodríguez

et al. 2024

IJMS

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Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist Giardia lamblia, which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Giardia lamblia. Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents

Gaona-López,

Méndez-Álvarez,

Moreno-Rodríguez

et al. 2024

IJMS

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Long non-coding RNAs as possible therapeutic targets in protozoa, and in Schistosoma and other helminths

Silveira,

Coelho,

Amaral

et al. 2021

Parasitol Res

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Low nucleotide diversity of the Plasmodium falciparum AP2-EXP2 gene among clinical samples from Ghana

Quansah,

Zhao,

Eduful

et al. 2024

Parasites Vectors

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Background PfAP2-EXP2 is located within chromosome 6 of Plasmodium falciparum recently identified to be undergoing an extensive selective sweep in West African isolates. The gene encoding this transcription factor, PfAP2-EXP2, is essential and thus likely subject to purifying selection that limits variants in the parasite population despite its genomic location. Methods 72 Plasmodium falciparum field samples and 801 clinical sequences from the Pf6 MalariaGEN dataset of Ghanaian origin, were integrated and analysed. Results A total of 14 single nucleotide variants of which 5 were missense variants, were identified after quality checks and filtering. Except for one, all identified variants were rare among the clinical samples obtained in this study (Minor allelic frequency < 0.01). Further results revealed a considerably low dN/dS value (0.208) suggesting the presence of purifying selection. Further, all the mutant amino acids were wildtype residues in AP2-EXP2 orthologous proteins—tentatively suggesting a genus-level conservation of amino acid residues. Computational analysis and predictions corroborated these findings. Conclusions Despite the recent extensive selective sweep within chromosome 6 of West African isolates, PfAP2-EXP2 of Ghanaian origin exhibits low nucleotide diversity and very low dN/dS consistent with purifying selection acting to maintain the function of an essential gene. The conservation of AP2-EXP2 is an important factor that makes it a potential drug target. Graphical Abstract

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Target acquired: transcriptional regulators as drug targets for protozoan parasites

Cited by 4 publications

References 78 publications

TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents

TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents

Long non-coding RNAs as possible therapeutic targets in protozoa, and in Schistosoma and other helminths

Low nucleotide diversity of the Plasmodium falciparum AP2-EXP2 gene among clinical samples from Ghana

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