Update on the biological relevance of lysine acetylation as a novel drug target in trypanosomatids

2021 ◽  
Vol 28 ◽  
Author(s):  
Gonzalo Martinez Peralta ◽  
Esteban Serra ◽  
Victoria Lucia Alonso
Keyword(s):  
Signaling Pathways ◽  
Drug Target ◽  
Rational Design ◽  
Review Article ◽  
Lysine Acetylation ◽  
Nuclear Compartment ◽  
Biological Relevance ◽  
Regulatory Functions ◽  
Novel Drug ◽  
Potential Use

: The number of acetylated proteins identified from bacteria to mammals has grown exponentially in the last ten years and it is now accepted that acetylation is a key component in most eukaryotic signaling pathways, as important as phosphorylation. The enzymes involved in this process are well described in mammals; acetyltransferases and deacetylases are found inside and outside the nuclear compartment and have different regulatory functions. In trypanosomatids several of these enzymes have been described and are postulated to be novel antiparasitic targets for the rational design of drugs. In this review article we present an update of the most important known acetylated proteins in trypanosomatids analyzing the acetylomes available. Also, we summarize the information available regarding acetyltransferases and deacetylases in trypanosomes and their potential use as chemotherapeutic targets.

scholarly journals Lysine Acetylation: Elucidating the Components of an Emerging Global Signaling Pathway in Trypanosomes

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Victoria Lucia Alonso ◽  
Esteban Carlos Serra
Keyword(s):  
Mass Spectrometry ◽  
Rational Design ◽  
High Resolution Mass Spectrometry ◽  
Lysine Acetylation ◽  
Nuclear Compartment ◽  
The Past ◽  
Regulatory Functions ◽  
Potential Use ◽  
Resolution Mass ◽  
Made In

In the past ten years the number of acetylated proteins reported in literature grew exponentially. Several authors have proposed that acetylation might be a key component in most eukaryotic signaling pathways, as important as phosphorylation. The enzymes involved in this process are starting to emerge; acetyltransferases and deacetylases are found inside and outside the nuclear compartment and have different regulatory functions. In trypanosomatids several of these enzymes have been described and are postulated to be novel antiparasitic targets for the rational design of drugs. In this paper we overview the most important known acetylated proteins and the advances made in the identification of new acetylated proteins using high-resolution mass spectrometry. Also, we summarize what is known so far about the acetyltransferases and deacetylases in eukaryotes, focusing on trypanosomes and their potential use as chemotherapeutic targets.

Identification of Antineoplastic Targets with Systems Approaches, Using Resveratrol as an In-Depth Case Study

2017 ◽  
Vol 23 (32) ◽  
pp. 4773-4793 ◽  
Author(s):  
Nivedita Singh ◽  
Sherry Freiesleben ◽  
Olaf Wolkenhauer ◽  
Yogeshwer Shukla ◽  
Shailendra K. Gupta
Keyword(s):  
Drug Target ◽  
Complex Disease ◽  
Biological Targets ◽  
Systems Approaches ◽  
Anticancer Mechanism ◽  
Genetic And Environmental Factors ◽  
Key Steps ◽  
Network Approaches ◽  
Novel Drug

The identification and validation of novel drug–target combinations are key steps in the drug discovery processes. Cancer is a complex disease that involves several genetic and environmental factors. High-throughput omics technologies are now widely available, however the integration of multi-omics data to identify viable anticancer drug-target combinations, that allow for a better clinical outcome when considering the efficacy-toxicity spectrum, is challenging. This review article provides an overview of systems approaches which help to integrate a broad spectrum of technologies and data. We focus on network approaches and investigate anticancer mechanism and biological targets of resveratrol using reverse pharmacophore mapping as an in-depth case study. The results of this case study demonstrate the use of systems approaches for a better understanding of the behavior of small molecule inhibitors in receptor binding sites. The presented network analysis approach helps in formulating hypotheses and provides mechanistic insights of resveratrol in neoplastic transformations.

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

Iron in parasitic protists – from uptake to storage and where we can interfere

Metallomics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1335-1347
Author(s):  
Jan Mach ◽  
Robert Sutak
Keyword(s):  
Iron Metabolism ◽  
Drug Target ◽  
Comprehensive Review ◽  
Potential Use

A comprehensive review of iron metabolism in parasitic protists and its potential use as a drug target.

scholarly journals Integrated network analysis identifying potential novel drug candidates and targets for Parkinson's disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pusheng Quan ◽  
Kai Wang ◽  
Shi Yan ◽  
Shirong Wen ◽  
Chengqun Wei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Target ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Control Group ◽  
Drug Candidates ◽  
Novel Drug

AbstractThis study aimed to identify potential novel drug candidates and targets for Parkinson’s disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

Drug–target prediction utilizing heterogeneous bio-linked network embeddings

2019 ◽  
Author(s):  
Nansu Zong ◽  
Rachael Sze Nga Wong ◽  
Yue Yu ◽  
Andrew Wen ◽  
Ming Huang ◽  
...  
Keyword(s):  
Drug Target ◽  
Target Prediction ◽  
Machine Learning Algorithms ◽  
Association Mining ◽  
Drug Target Prediction ◽  
Specific Prediction ◽  
Series Of Experiments ◽  
Inference Methods ◽  
Novel Drug ◽  
Prediction Strategy

Abstract To enable modularization for network-based prediction, we conducted a review of known methods conducting the various subtasks corresponding to the creation of a drug–target prediction framework and associated benchmarking to determine the highest-performing approaches. Accordingly, our contributions are as follows: (i) from a network perspective, we benchmarked the association-mining performance of 32 distinct subnetwork permutations, arranging based on a comprehensive heterogeneous biomedical network derived from 12 repositories; (ii) from a methodological perspective, we identified the best prediction strategy based on a review of combinations of the components with off-the-shelf classification, inference methods and graph embedding methods. Our benchmarking strategy consisted of two series of experiments, totaling six distinct tasks from the two perspectives, to determine the best prediction. We demonstrated that the proposed method outperformed the existing network-based methods as well as how combinatorial networks and methodologies can influence the prediction. In addition, we conducted disease-specific prediction tasks for 20 distinct diseases and showed the reliability of the strategy in predicting 75 novel drug–target associations as shown by a validation utilizing DrugBank 5.1.0. In particular, we revealed a connection of the network topology with the biological explanations for predicting the diseases, ‘Asthma’ ‘Hypertension’, and ‘Dementia’. The results of our benchmarking produced knowledge on a network-based prediction framework with the modularization of the feature selection and association prediction, which can be easily adapted and extended to other feature sources or machine learning algorithms as well as a performed baseline to comprehensively evaluate the utility of incorporating varying data sources.

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