Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

2019 ◽  
Vol 19 (6) ◽  
pp. 430-448 ◽  
Author(s):  
Khalid Bashir Dar ◽  
Aashiq Hussain Bhat ◽  
Shajrul Amin ◽  
Syed Anjum ◽  
Bilal Ahmad Reshi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Critical Role ◽  
Cancer Therapeutics ◽  
Adaptor Proteins ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Beta Catenin ◽  
Protein Protein Interactions ◽  
Apoptosis Protein

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

Engineering “Antimicrobial Peptides” and Other Peptides to Modulate Protein-Protein Interactions in Cancer

2020 ◽  
Vol 20 (32) ◽  
pp. 2970-2983
Author(s):  
Samuel J.S. Rubin ◽  
Nir Qvit
Keyword(s):  
Antimicrobial Peptides ◽  
Protein Interactions ◽  
Anticancer Agents ◽  
Cancer Therapeutics ◽  
Target Cells ◽  
Protein Protein Interactions ◽  
Peptide Backbone ◽  
Modified Peptides ◽  
Selective Death ◽  
Drug Leads

Antimicrobial peptides (AMPs) are a class of peptides found across a wide array of organisms that play key roles in host defense. AMPs induce selective death in target cells and orchestrate specific or nonspecific immune responses. Many AMPs exhibit native anticancer activity in addition to antibacterial activity, and others have been engineered as antineoplastic agents. We discuss the use of AMPs in the detection and treatment of cancer as well as mechanisms of AMP-induced cell death. We present key examples of cathelicidins and transferrins, which are major AMP families. Further, we discuss the critical roles of protein-protein interactions (PPIs) in cancer and how AMPs are well-suited to target PPIs based on their unique drug-like properties not exhibited by small molecules or antibodies. While peptides, including AMPs, can have limited stability and bioavailability, these issues can be overcome by peptide backbone modification or cyclization (e.g., stapling) and by the use of delivery systems such as cellpenetrating peptides (CPPs), respectively. We discuss approaches for optimizing drug properties of peptide and peptidomimetic leads (modified peptides), providing examples of promising techniques that may be applied to AMPs. These molecules represent an exciting resource as anticancer agents with unique therapeutic advantages that can target challenging mechanisms involving PPIs. Indeed, AMPs are suitable drug leads for further development of cancer therapeutics, and many studies to this end are underway.

scholarly journals Coiled-coil networking shapes cell molecular machinery

2012 ◽  
Vol 23 (19) ◽  
pp. 3911-3922 ◽  
Author(s):  
Yongqiang Wang ◽  
Xinlei Zhang ◽  
Hong Zhang ◽  
Yi Lu ◽  
Haolong Huang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Critical Role ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Protein Protein Interactions ◽  
Full Spectrum ◽  
Kinetochore Assembly ◽  
Genome Wide ◽  
Molecular Machinery ◽  
Systematic Understanding

The highly abundant α-helical coiled-coil motif not only mediates crucial protein–protein interactions in the cell but is also an attractive scaffold in synthetic biology and material science and a potential target for disease intervention. Therefore a systematic understanding of the coiled-coil interactions (CCIs) at the organismal level would help unravel the full spectrum of the biological function of this interaction motif and facilitate its application in therapeutics. We report the first identified genome-wide CCI network in Saccharomyces cerevisiae, which consists of 3495 pair-wise interactions among 598 predicted coiled-coil regions. Computational analysis revealed that the CCI network is specifically and functionally organized and extensively involved in the organization of cell machinery. We further show that CCIs play a critical role in the assembly of the kinetochore, and disruption of the CCI network leads to defects in kinetochore assembly and cell division. The CCI network identified in this study is a valuable resource for systematic characterization of coiled coils in the shaping and regulation of a host of cellular machineries and provides a basis for the utilization of coiled coils as domain-based probes for network perturbation and pharmacological applications.

scholarly journals Practical Model Selection for Prospective Virtual Screening

2018 ◽  
Author(s):  
Shengchao Liu ◽  
Moayad Alnammi ◽  
Spencer S. Ericksen ◽  
Andrew F. Voter ◽  
Gene E. Ananiev ◽  
...  
Keyword(s):  
Random Forest ◽  
Virtual Screening ◽  
Protein Interactions ◽  
High Throughput Screening ◽  
Screening Methods ◽  
Protein Protein Interactions ◽  
Screening Algorithm ◽  
Screening Performance ◽  
Wide Range ◽  
Public Datasets

AbstractVirtual (computational) high-throughput screening provides a strategy for prioritizing compounds for experimental screens, but the choice of virtual screening algorithm depends on the dataset and evaluation strategy. We consider a wide range of ligand-based machine learning and docking-based approaches for virtual screening on two protein-protein interactions, PriA-SSB and RMI-FANCM, and present a strategy for choosing which algorithm is best for prospective compound prioritization. Our workflow identifies a random forest as the best algorithm for these targets over more sophisticated neural network-based models. The top 250 predictions from our selected random forest recover 37 of the 54 active compounds from a library of 22,434 new molecules assayed on PriA-SSB. We show that virtual screening methods that perform well in public datasets and synthetic benchmarks, like multi-task neural networks, may not always translate to prospective screening performance on a specific assay of interest.

scholarly journals Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update

2022 ◽  
Vol 23 (2) ◽  
pp. 840
Author(s):  
Li-Min Mao ◽  
Alaya Bodepudi ◽  
Xiang-Ping Chu ◽  
John Q. Wang
Keyword(s):  
Synaptic Plasticity ◽  
Protein Interactions ◽  
Metabotropic Glutamate Receptors ◽  
Adaptor Proteins ◽  
Mammalian Brain ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Associated Proteins

Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

scholarly journals The Role of WAVE2 Signaling in Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1217
Author(s):  
Priyanka Shailendra Rana ◽  
Akram Alkrekshi ◽  
Wei Wang ◽  
Vesna Markovic ◽  
Khalid Sossey-Alaoui
Keyword(s):  
Actin Cytoskeleton ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Critical Role ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Cancer Cell Invasion ◽  
Invasion And Metastasis ◽  
Regulatory Complex

The Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)—WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.

scholarly journals Mitochondria: Regulators of Cell Death and Survival

2002 ◽  
Vol 2 ◽  
pp. 1569-1578 ◽  
Author(s):  
David J. Granville ◽  
Roberta A. Gottlieb
Keyword(s):  
Cell Death ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Death Process ◽  
Protein Protein Interactions ◽  
Ionic Changes ◽  
A Cell ◽  
Cyt C

The past 5 years has seen an intense surge in research devoted toward understanding the critical role of mitochondria in the regulation of cell death. Apoptosis can be initiated by a wide array of stimuli, inducing multiple signaling pathways that, for the most part, converge at the mitochondrion. Although classically considered the powerhouses of the cell, it is now understood that mitochondria are also “gatekeepers” that ultimately determine the fate of the cell. The mitochondrial decision as to whether a cell lives or dies is complex, involving protein-protein interactions, ionic changes, reactive oxygen species, and other mechanisms that require further elucidation. Once the death process is initiated, mitochondria undergo conformational changes, resulting in the release of cytochrome c (cyt c), caspases, endonucleases, and other factors leading to the onset and execution of apoptosis. The present review attempts to outline the complex milieu of events regulating the mitochondrial commitment to and processes involved in the implementation of the executioner phase of apoptotic cell death.

scholarly journals Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1579 ◽  
Author(s):  
Ainsley Mike Antao ◽  
Apoorvi Tyagi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Protein Interactions ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Protein Protein Interactions ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Target Cancer

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

scholarly journals Signaling Protein Networks as Targets of New Antineoplastic Drugs

2003 ◽  
Vol 18 (1) ◽  
pp. 57-61 ◽  
Author(s):  
S. Alberti ◽  
S. Parodi
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Regulatory Networks ◽  
Signaling Proteins ◽  
Protein Protein Interactions ◽  
Therapeutic Approaches ◽  
Chemical Libraries ◽  
Drug Candidates ◽  
Microbial Extracts ◽  
Depth Analysis

In-depth analysis of molecular regulatory networks in cancer holds the promise of improved knowledge of the pathophysiology of tumor cells so that it will become possible to design a detailed molecular tumor taxonomy. This knowledge will also offer new opportunities for the identification and validation of key molecular tumor targets to be exploited for novel therapeutic approaches. Some signaling proteins have already been identified as such, e.g. c-Myc, Cyclin D1, Bcl-XL, kinases and some nuclear receptors. This has led to the successful development of a few function-modulatory drugs (Glivec, SERM, Iressa), providing proof-of-principle of the validity of this approach. Further developments are likely to derive from “-omic” approaches, aimed at the understanding of signaling networks and of the mechanism of action of newfound lead molecules. High-throughput screening of small drug-like molecules from combinatorial chemical libraries or from microbial extracts will identify novel, “intelligent” drug candidates. An additional medicinal chemistry strategy (via 40–50 unit rosary-bead chains) has the potential to be much more effective than small molecules in interfering with protein-protein interactions. This may lead to considerably higher selectivity and effectiveness compared with historical approaches in drug discovery.

scholarly journals Proteomic analysis of palmitoylated platelet proteins

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. e62-e73 ◽  
Author(s):  
Louisa Dowal ◽  
Wei Yang ◽  
Michael R. Freeman ◽  
Hanno Steen ◽  
Robert Flaumenhaft
Keyword(s):  
Protein Interactions ◽  
Protein Identification ◽  
Global Analysis ◽  
Critical Role ◽  
Myeloid Cell ◽  
Metabolic Labeling ◽  
Protein Protein Interactions ◽  
Proteomic Approach ◽  
Protein Palmitoylation ◽  
Liquid Chromatography Tandem Mass

Abstract Protein palmitoylation is a dynamic process that regulates membrane targeting of proteins and protein-protein interactions. We have previously demonstrated a critical role for protein palmitoylation in platelet activation and have identified palmitoylation machinery in platelets. Using a novel proteomic approach, Palmitoyl Protein Identification and Site Characterization, we have begun to characterize the human platelet palmitoylome. Palmitoylated proteins were enriched from membranes isolated from resting platelets using acyl-biotinyl exchange chemistry, followed by identification using liquid chromatography-tandem mass spectrometry. This global analysis identified > 1300 proteins, of which 215 met criteria for significance and represent the platelet palmitoylome. This collection includes 51 known palmitoylated proteins, 61 putative palmitoylated proteins identified in other palmitoylation-specific proteomic studies, and 103 new putative palmitoylated proteins. Of these candidates, we chose to validate the palmitoylation of triggering receptors expressed on myeloid cell (TREM)–like transcript-1 (TLT-1) as its expression is restricted to platelets and megakaryocytes. We determined that TLT-1 is a palmitoylated protein using metabolic labeling with [3H]palmitate and identified the site of TLT-1 palmitoylation as cysteine 196. The discovery of new platelet palmitoyl protein candidates will provide a resource for subsequent investigations to validate the palmitoylation of these proteins and to determine the role palmitoylation plays in their function.

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