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.

scholarly journals Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Fabian Hulpia ◽  
Dorien Mabille ◽  
Gustavo D. Campagnaro ◽  
Gabriela Schumann ◽  
Louis Maes ◽  
...  
Keyword(s):  
Late Stage ◽  
De Novo ◽  
Treatment Options ◽  
Pool Analysis ◽  
Sleeping Sickness ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Nucleoside Transporter ◽  
African Trypanosomes

AbstractAfrican trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3’-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3’-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3’-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness.

Protein Glycation: An Old Villain is Shedding Secrets

2019 ◽  
Vol 22 (6) ◽  
pp. 362-369
Author(s):  
Gerald H. Lushington ◽  
Anthony C. Barnes
Keyword(s):  
Drug Targets ◽  
Current Knowledge ◽  
Treatment Options ◽  
Protein Glycation ◽  
Target Area ◽  
Disease Etiology ◽  
Glycated Proteins ◽  
Parkinson’S Diseases ◽  
Challenges And Opportunities ◽  
Novel Drug

: The glycation of proteins is non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained widespread acceptance as a contributing factor in numerous metabolic, autoimmune, and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis, and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s diseases, an emerging glycation/inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs. : This ‘current frontier’ article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications, and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.

scholarly journals Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

2014 ◽  
Author(s):  
N. Susantha Chandrasekera ◽  
Mai A Bailey ◽  
Megan Files ◽  
Torey Alling ◽  
Stephanie K Florio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Mode Of Action ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Eukaryotic Cells ◽  
Structure Activity ◽  
Novel Drug ◽  
Further Development ◽  
Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

scholarly journals Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

2014 ◽  
Author(s):  
N. Susantha Chandrasekera ◽  
Mai A Bailey ◽  
Megan Files ◽  
Torey Alling ◽  
Stephanie K Florio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Mode Of Action ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Eukaryotic Cells ◽  
Structure Activity ◽  
Novel Drug ◽  
Further Development ◽  
Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

scholarly journals Adenosine Kinase of Trypanosoma brucei and Its Role in Susceptibility to Adenosine Antimetabolites

2007 ◽  
Vol 51 (11) ◽  
pp. 3895-3901 ◽  
Author(s):  
Alexandra Lüscher ◽  
Pinar Önal ◽  
Anne-Marie Schweingruber ◽  
Pascal Mäser
Keyword(s):  
Trypanosoma Brucei ◽  
De Novo ◽  
Growth Conditions ◽  
Adenosine Kinase ◽  
Bloodstream Form ◽  
Null Mutation ◽  
Transporter Gene ◽  
Purine Salvage ◽  
Kinase Gene ◽  
Pharmacological Interest

ABSTRACT Trypanosoma brucei cannot synthesize purines de novo and relies on purine salvage from its hosts to build nucleic acids. With adenosine being a preferred purine source of bloodstream-form trypanosomes, adenosine kinase (AK; EC 2.7.1.20) is likely to be a key player in purine salvage. Adenosine kinase is also of high pharmacological interest, since for many adenosine antimetabolites, phosphorylation is a prerequisite for activity. Here, we cloned and functionally characterized adenosine kinase from T. brucei (TbAK). TbAK is a tandem gene, expressed in both procyclic- and bloodstream-form trypanosomes, whose product localized to the cytosol of the parasites. The RNA interference-mediated silencing of TbAK suggested that the gene is nonessential under standard growth conditions. Inhibition or downregulation of TbAK rendered the trypanosomes resistant to cordycepin (3′-deoxyadenosine), demonstrating a role for TbAK in the activation of adenosine antimetabolites. The expression of TbAK in Saccharomyces cerevisiae complemented a null mutation in the adenosine kinase gene ado1. The concomitant expression of TbAK with the T. brucei adenosine transporter gene TbAT1 allowed S. cerevisiae ado1 ade2 double mutants to grow on adenosine as the sole purine source and, at the same time, sensitized them to adenosine antimetabolites. The coexpression of TbAK and TbAT1 in S. cerevisiae ado1 ade2 double mutants proved to be a convenient tool for testing nucleoside analogues for uptake and activation by T. brucei adenosine salvage enzymes.

scholarly journals AIP and its interacting partners

2011 ◽  
Vol 210 (2) ◽  
pp. 137-155 ◽  
Author(s):  
Giampaolo Trivellin ◽  
Márta Korbonits
Keyword(s):  
Drug Targets ◽  
Heat Shock Protein 90 ◽  
Pituitary Tumour ◽  
Pathological Process ◽  
Loss Of Function ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Tumour Formation ◽  
Α Helix ◽  
Novel Drug

Germline mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to young-onset pituitary tumours, most often to GH- or prolactin-secreting adenomas, and most of these patients belong to familial isolated pituitary adenoma families. The molecular pathway initiated by the loss-of-function AIP mutations leading to pituitary tumour formation is unknown. AIP, a co-chaperone of heat-shock protein 90 and various nuclear receptors, belongs to the family of tetratricopeptide repeat (TPR)-containing proteins. It has three antiparallel α-helix motifs (TPR domains) that mediate the interaction of AIP with most of its partners. In this review, we summarise the known interactions of AIP described so far. The identification of AIP partners and the understanding of how AIP interacts with these proteins might help to explain the specific phenotype of the families with heterozygous AIP mutations, to gain deeper insight into the pathological process of pituitary tumour formation and to identify novel drug targets.

scholarly journals Molecular Network Approach Reveals Rictor as a Central Target of Cardiac ProtectomiRs

2021 ◽  
Vol 22 (17) ◽  
pp. 9539
Author(s):  
András Makkos ◽  
Bence Ágg ◽  
Zoltán V. Varga ◽  
Zoltán Giricz ◽  
Mariann Gyöngyösi ◽  
...  
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Target Genes ◽  
Ischemic Postconditioning ◽  
Molecular Network ◽  
Pig Model ◽  
Node Degree ◽  
Central Target ◽  
Mrna Targets ◽  
Novel Drug

Cardioprotective medications are still unmet clinical needs. We have previously identified several cardioprotective microRNAs (termed ProtectomiRs), the mRNA targets of which may reveal new drug targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction (AMI). By using a network theoretical approach, we identified 882 potential target genes of 18 previously identified protectomiRs. The Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of AMI and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning. This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.

scholarly journals Updates in the Systemic Treatment of Hepatocellular Carcinoma

2018 ◽  
Vol 14 (2) ◽  
pp. 76
Author(s):  
Emerson Y Chen ◽  
Charles D Lopez ◽  
Gina M Vaccaro ◽  
◽  
◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Targets ◽  
Systemic Treatment ◽  
Treatment Options ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Recent Phase ◽  
Novel Drug ◽  
Near Future ◽  
Novel Drug Targets

Oncology drug development has recently introduced new systemic treatment options for hepatocellular carcinoma (HCC). Here we consider the general approaches to diagnostic workup, staging, and overall management of HCC with emphasis on systemic treatment options based on recent phase III clinical trials. Novel drug targets involving immunotherapy may change how we treat HCC in the near future.

scholarly journals Knowledge graph analytics platform with LINCS and IDG for Parkinson's disease target illumination

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Jeremy J. Yang ◽  
Christopher R. Gessner ◽  
Joel L. Duerksen ◽  
Daniel Biber ◽  
Jessica L. Binder ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Human Health ◽  
Molecular Basis ◽  
Drug Target ◽  
Drug Targets ◽  
Complex Diseases ◽  
Knowledge Graph ◽  
Graph Analytics ◽  
Novel Drug ◽  
Novel Drug Targets

Abstract Background LINCS, "Library of Integrated Network-based Cellular Signatures", and IDG, "Illuminating the Druggable Genome", are both NIH projects and consortia that have generated rich datasets for the study of the molecular basis of human health and disease. LINCS L1000 expression signatures provide unbiased systems/omics experimental evidence. IDG provides compiled and curated knowledge for illumination and prioritization of novel drug target hypotheses. Together, these resources can support a powerful new approach to identifying novel drug targets for complex diseases, such as Parkinson's disease (PD), which continues to inflict severe harm on human health, and resist traditional research approaches. Results Integrating LINCS and IDG, we built the Knowledge Graph Analytics Platform (KGAP) to support an important use case: identification and prioritization of drug target hypotheses for associated diseases. The KGAP approach includes strong semantics interpretable by domain scientists and a robust, high performance implementation of a graph database and related analytical methods. Illustrating the value of our approach, we investigated results from queries relevant to PD. Approved PD drug indications from IDG’s resource DrugCentral were used as starting points for evidence paths exploring chemogenomic space via LINCS expression signatures for associated genes, evaluated as target hypotheses by integration with IDG. The KG-analytic scoring function was validated against a gold standard dataset of genes associated with PD as elucidated, published mechanism-of-action drug targets, also from DrugCentral. IDG's resource TIN-X was used to rank and filter KGAP results for novel PD targets, and one, SYNGR3 (Synaptogyrin-3), was manually investigated further as a case study and plausible new drug target for PD. Conclusions The synergy of LINCS and IDG, via KG methods, empowers graph analytics methods for the investigation of the molecular basis of complex diseases, and specifically for identification and prioritization of novel drug targets. The KGAP approach enables downstream applications via integration with resources similarly aligned with modern KG methodology. The generality of the approach indicates that KGAP is applicable to many disease areas, in addition to PD, the focus of this paper.

scholarly journals In-silico Identification of Novel Drug Target for Osteoarthritisinhuman using System Network Biology Approaches

2020 ◽  
Author(s):  
Neha srivastava ◽  
Nityendra Shukla ◽  
Aditya Trivedi ◽  
Dr Prachi srivastava ◽  
Prof Prahlad Kishore Seth
Keyword(s):  
Drug Target ◽  
Treatment Options ◽  
Network Biology ◽  
Ppi Network ◽  
Joint Injury ◽  
Obesity Epidemic ◽  
Protein Protein Interaction ◽  
In Silico Identification ◽  
Disease Modifying Treatment ◽  
Novel Drug

<p>Osteoarthritis (OA) is the most common form of joint disability in the world affecting a large number of persons s yet the mechanisms responsible for the disease is not well n understood. And therefore there is a lack of disease-modifying treatment options. It has several risk factors from systemic (e.g. age, sex, genetics, obesity) to biochemical factors (e.g. joint injury, muscle weakness, sport). The prevalence of OA is ever increasing due to the obesity epidemic and longevity. Since OA has strong genetic predisposition, in the study we attempted system network biology approach to identify a key candidate gene in a protein-protein interaction (PPI) network of OA, which may play an important role in disease pathogenesis and help us to understand the development and progression of the disease. This information will help in target specific development of new molecules which may eventually lead to curative solutions for OA in human.</p>

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