scholarly journals Developing drugs for the ‘undruggable’

BioTechniques ◽  
2020 ◽  
Vol 69 (4) ◽  
pp. 239-241
Author(s):  
Abigail Sawyer
Keyword(s):  
Protein Interactions ◽  
Therapeutic Targets ◽  
Protein Protein Interactions ◽  
Human Interactome ◽  
Novel Therapeutic

There are up to 650,000 ‘undruggable’ protein-protein interactions (PPIs) in the human interactome that can be potentially considered as novel therapeutic targets. How does the ‘undruggable’ become ‘druggable’?

Inhibition of bromodomain-mediated protein–protein interactions as a novel therapeutic strategy

MedChemComm ◽  
2012 ◽  
Vol 3 (2) ◽  
pp. 123-134 ◽  
Author(s):  
Silviya D. Furdas ◽  
Luca Carlino ◽  
Wolfgang Sippl ◽  
Manfred Jung
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Therapeutic Strategy ◽  
Small Molecule Inhibitors ◽  
Protein Protein Interactions ◽  
Therapeutic Approaches ◽  
Novel Therapeutic

Small molecule inhibitors of acetyl lysine–bromodomain interactions emerge as novel epigenetic tools with potential for therapeutic approaches.

scholarly journals Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling

2021 ◽  
Author(s):  
Shuhui Lim ◽  
Nicolas Boyer ◽  
Nicole Boo ◽  
Chunhui Huang ◽  
Gireedhar Venkatachalam ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Therapeutic Targets ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Macrocyclic Peptides

Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons...

scholarly journals Latest update on chemokine receptors as therapeutic targets

2021 ◽  
Author(s):  
Wing Yee Lai ◽  
Anja Mueller
Keyword(s):  
Protein Interactions ◽  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Specific Binding ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Fine Tuning ◽  
Protein Protein Interactions ◽  
Diverse Range ◽  
Chemokine Ligand

The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand–receptor interactions and the downstream signalling protein–protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.

scholarly journals Dynamic rewiring of the human interactome by interferon signalling

2019 ◽  
Author(s):  
Craig H. Kerr ◽  
Michael A. Skinnider ◽  
Angel M. Madero ◽  
Daniel D.T. Andrews ◽  
R. Greg Stacey ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Interaction Network ◽  
Cell Types ◽  
Antiviral Response ◽  
Type I ◽  
Protein Protein Interactions ◽  
Human Interactome ◽  
Viral Pathogens ◽  
Protein Protein Interaction ◽  
Dependent Protein

ABSTRACTBackgroundThe type I interferon (IFN) response is an ancient pathway that protects cells against viral pathogens by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). Transcriptomic and biochemical approaches have established comprehensive catalogues of ISGs across species and cell types, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to delineate the effects of IFN signalling on the human proteome, culminating in the use of protein correlation profiling to map IFN-induced rearrangements in the human protein-protein interaction network.ResultsWe identified >27,000 protein interactions in IFN-stimulated and unstimulated cells, many of which involve proteins associated with human disease and are observed exclusively within the IFN-stimulated network. Differential network analysis reveals interaction rewiring across a surprisingly broad spectrum of cellular pathways in the antiviral response. We identify IFN-dependent protein-protein interactions mediating novel regulatory mechanisms at the transcriptional and translational levels, with one such interaction modulating the transcriptional activity of STAT1. Moreover, we reveal IFN-dependent changes in ribosomal composition that act to buffer ISG protein synthesis.ConclusionsOur map of the IFN interactome provides a global view of the complex cellular networks activated during the antiviral response, placing ISGs in a functional context, and serves as a framework to understand how these networks are dysregulated in autoimmune or inflammatory disease.

Abstract 1122‐000102: Function of Proteins Predictive of Infarct Volume in Mechanical Thrombectomy Subjects

2021 ◽  
Vol 1 (S1) ◽  
Author(s):  
Benton Maglinger ◽  
Christopher McLouth ◽  
Chintan Rupareliya ◽  
Jacqueline Frank ◽  
Madison Sands ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Protein Interactions ◽  
Mechanical Thrombectomy ◽  
Infarct Volume ◽  
Therapeutic Targets ◽  
Translation Initiation Factor ◽  
Protein Protein Interactions ◽  
Vascular Events ◽  
Positive Regulation ◽  
P Values

Introduction : Emergent Large Vessel Occlusion (ELVO) strokes are devastating ischemic vascular events which can cause severe and permanent impairment. The purpose of this study is to investigate protein‐protein interactions at the time of mechanical thrombectomy (MT) which correlate to infarct volume. Uncovering functions of protein‐protein interactions involved in infarct volume will allow for biomarker discovery and potential therapeutic targets. Methods : The Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC) is a continually enrolling tissue bank (clinicaltrials.gov NCT03153683) from stroke patients undergoing MT. N = 61 human carotid plasma samples were analyzed for inflammatory and cardiometabolic protein expression by Olink Proteomics. To determine which proteins had the most significant changes based on infarct volume, a series of 184 paired t‐tests were performed. Within each panel, proteins were then ranked based on the associated p‐values. Benjamini and Hochberg’s linear step‐up procedure was used to control the false discovery rate at 0.05. Pearson correlation revealed proteins which were most significantly related to infarct volume. STRING analysis was used to identify protein‐protein network and biologic functions. Results : Systemic proteins most predictive of infarct volume included adenosine deaminase (ADA), monocyte chemotactic protein 1 (MCP1), eukaryotic translation initiation factor binding protein (EBP1), Nidogen‐1 (NID1), CD40, and leukemia inhibitory factor receptor (LIFR). All correlations between each protein and infarct volume were positive in directionality and were statistically significant with p‐values less than 0.05. STRING output demonstrated relevant biological functions including ‘positive regulation of signal transduction,’ ‘cytokine mediated signaling,’ ‘positive regulation of NFkB transcription factor activity,’ and ‘tumor necrosis factor signaling pathways.’ Conclusions : This study identified proteins predictive of infarct volume at time of MT in ELVO patients. LIF is a cytokine in the IL‐6 family that has been shown to play a role in inflammation and ischemia. ADA deaminates adenosine, which inactivates its neuroprotective property in acute cerebral ischemia. Higher levels of circulating MCP1 have been shown to be associated with increased risk of stroke. These proteomic signaling networks and functions inform the biochemical picture involved in the pathogenesis and outcome of cerebral ischemia. Importantly, these proteins serve as biomarker candidates and possible therapeutic targets.

scholarly journals BIRC3 and BIRC5: multi‐faceted inhibitors in cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raffaele Frazzi
Keyword(s):  
Cancer Cells ◽  
Protein Interactions ◽  
Point Mutations ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Main Body ◽  
Protein Protein Interactions ◽  
Smac Mimetics

Abstract Background The evasion from apoptosis is a common strategy adopted by most tumors, and inhibitors of apoptosis proteins (IAPs) are among the most studied molecular and therapeutic targets. BIRC3 (cellular IAP2) and BIRC5 (survivin) are two of the eight members of the human IAPs family. This family is characterized by the presence of the baculoviral IAP repeat (BIR) domains, involved in protein-protein interactions. In addition to the BIR domains, IAPs also contain other important domains like the C-terminal ubiquitin-conjugating (UBC) domain, the caspase recruitment (CARD) domain and the C-terminal Ring zinc-finger (RING) domain. Main body BIRC3 and BIRC5 have been characterized in some solid and hematological tumors and are therapeutic targets for the family of drugs called “Smac mimetics”. Many evidences point to the pro-survival and antiapoptotic role of BIRC3 in cancer cells, however, not all the data are consistent and the resulting picture is heterogeneous. For instance, BIRC3 genetic inactivation due to deletions or point mutations is consistently associated to shorter progression free survival and poor prognosis in chronic lymphocytic leukemia patients. BIRC3 inactivation has also been associated to chemoimmunotherapy resistance. On the contrary, the progression from low grade gliomas to high grade gliomas is accompanied by BIRC3 expression increase, which bears relevant prognostic consequences. Due to the relationship between BIRC3, MAP3K14 and the non-canonical NF-kB pathway, BIRC3 inactivation bears consequences also on the tumor cells relying on NF-kB pathway to survive. BIRC5, on the contrary, is commonly considered an anti-apoptotic molecule, promoting cell division and tumor progression and it is widely regarded as potential therapeutic target. Conclusions The present manuscript collects and reviews the most recent literature concerning the role played by BIRC3 and BIRC5 in cancer cells, providing useful information for the choice of the best therapeutic targets.

scholarly journals Computational Prediction of Biomarkers, Pathways, and New Target Drugs in the Pathogenesis of Immune-Based Diseases Regarding Kidney Transplantation Rejection

2021 ◽  
Vol 12 ◽  
Author(s):  
Rafael Alfaro ◽  
Helios Martínez-Banaclocha ◽  
Santiago Llorente ◽  
Victor Jimenez-Coll ◽  
José Antonio Galián ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Nk Cells ◽  
Protein Interactions ◽  
Graft Rejection ◽  
Therapeutic Targets ◽  
Protein Protein Interactions ◽  
Antibody Mediated Rejection ◽  
Biological Analysis ◽  
Expression Of Genes ◽  
Leukocyte Populations

BackgroundThe diagnosis of graft rejection in kidney transplantation (KT) patients is made by evaluating the histological characteristics of biopsy samples. The evolution of omics sciences and bioinformatics techniques has contributed to the advancement in searching and predicting biomarkers, pathways, and new target drugs that allow a more precise and less invasive diagnosis. The aim was to search for differentially expressed genes (DEGs) in patients with/without antibody-mediated rejection (AMR) and find essential cells involved in AMR, new target drugs, protein-protein interactions (PPI), and know their functional and biological analysis.Material and MethodsFour GEO databases of kidney biopsies of kidney transplantation with/without AMR were analyzed. The infiltrating leukocyte populations in the graft, new target drugs, protein-protein interactions (PPI), functional and biological analysis were studied by different bioinformatics tools.ResultsOur results show DEGs and the infiltrating leukocyte populations in the graft. There is an increase in the expression of genes related to different stages of the activation of the immune system, antigenic presentation such as antibody-mediated cytotoxicity, or leukocyte migration during AMR. The importance of the IRF/STAT1 pathways of response to IFN in controlling the expression of genes related to humoral rejection. The genes of this biological pathway were postulated as potential therapeutic targets and biomarkers of AMR. These biological processes correlated showed the infiltration of NK cells and monocytes towards the allograft. Besides the increase in dendritic cell maturation, it plays a central role in mediating the damage suffered by the graft during AMR. Computational approaches to the search for new therapeutic uses of approved target drugs also showed that imatinib might theoretically be helpful in KT for the prevention and/or treatment of AMR.ConclusionOur results suggest the importance of the IRF/STAT1 pathways in humoral kidney rejection. NK cells and monocytes in graft damage have an essential role during rejection, and imatinib improves KT outcomes. Our results will have to be validated for the potential use of overexpressed genes as rejection biomarkers that can be used as diagnostic and prognostic markers and as therapeutic targets to avoid graft rejection in patients undergoing kidney transplantation.

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