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Drug Discovery Today Jun 2022Proteases have crucial roles in homeostasis and disease; and protease inhibitors and recombinant proteases in enzyme replacement therapy have become key therapeutic... (Review)
Review
Proteases have crucial roles in homeostasis and disease; and protease inhibitors and recombinant proteases in enzyme replacement therapy have become key therapeutic applications of protease biology across several indications. This review briefly summarises therapeutic approaches based on protease activation and focuses on how recent insights into the spatial and temporal control of the proteolytic activation of growth factors and interleukins are leading to unique strategies for the discovery of new medicines. In particular, two emerging areas are covered: the first is based on antibody therapies that target the process of proteolytic activation of the pro-form of proteins rather than their mature form; the second covers a potentially new class of biopharmaceuticals using engineered, proteolytically activable and initially inactive pro-forms of antibodies or effector proteins to increase specificity and improve the therapeutic window.
Topics: Peptide Hydrolases; Protease Inhibitors; Proteolysis
PubMed: 35314338
DOI: 10.1016/j.drudis.2022.03.011 -
Cell and Tissue Research Aug 2021Proteases play a central role in regulating renal pathophysiology and are increasingly evaluated as actionable drug targets. Here, we review the role of proteolytic... (Review)
Review
Proteases play a central role in regulating renal pathophysiology and are increasingly evaluated as actionable drug targets. Here, we review the role of proteolytic systems in inflammatory kidney disease. Inflammatory kidney diseases are associated with broad dysregulations of extracellular and intracellular proteolysis. As an example of a proteolytic system, the complement system plays a significant role in glomerular inflammatory kidney disease and is currently under clinical investigation. Based on two glomerular kidney diseases, lupus nephritis, and membranous nephropathy, we portrait two proteolytic pathomechanisms and the role of the complement system. We discuss how profiling proteolytic activity in patient samples could be used to stratify patients for more targeted interventions in inflammatory kidney diseases. We also describe novel comprehensive, quantitative tools to investigate the entirety of proteolytic processes in a tissue sample. Emphasis is placed on mass spectrometric approaches that enable the comprehensive analysis of the complement system, as well as protease activities and regulation in general.
Topics: Animals; Humans; Inflammation; Kidney Glomerulus; Proteolysis
PubMed: 33864499
DOI: 10.1007/s00441-021-03433-8 -
Cell Chemical Biology Jul 2021Molecular glues and proteolysis targeting chimeras (PROTACs) have emerged as small-molecule tools that selectively induce the degradation of a chosen protein and have... (Review)
Review
Molecular glues and proteolysis targeting chimeras (PROTACs) have emerged as small-molecule tools that selectively induce the degradation of a chosen protein and have shown therapeutic promise. Recently, several approaches employing light as an additional stimulus to control induced protein degradation have been reported. Here, we analyze the principles guiding the design of such systems, provide a survey of the literature published to date, and discuss opportunities for further development. Light-responsive degraders enable the precise temporal and spatial control of protein levels, making them useful research tools but also potential candidates for human precision medicine.
Topics: Humans; Precision Medicine; Proteins; Proteolysis; Small Molecule Libraries
PubMed: 34115971
DOI: 10.1016/j.chembiol.2021.05.010 -
Cell Communication and Signaling : CCS Sep 2023Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous... (Review)
Review
Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous mitochondria-dependent and exogenous death receptor pathways, and studies have shown that caspase-8-dependent external pathways appear to be more important than the activity of the intrinsic pathways. This paper reviews the regulation of anoikis by external pathways mediated by death receptors. Different death receptors bind to different ligands to activate downstream caspases. The possible mechanisms of Fas-associated death domain (FADD) recruitment by Fas and TNF receptor 1 associated-death domain (TRADD) recruitment by tumor necrosis factor receptor 1 (TNFR1), and DR4- and DR5-associated FADD to induce downstream caspase activation and regulate anoikis were reviewed. This review highlights the possible mechanism of the death receptor pathway mediation of anoikis and provides new insights and research directions for studying tumor metastasis mechanisms. Video Abstract.
Topics: Anoikis; Proteolysis; Caspases; Mitochondria; Protein Processing, Post-Translational
PubMed: 37667281
DOI: 10.1186/s12964-023-01247-5 -
Biochemical Society Transactions Aug 2021Protein glycosylation is one of the most common post-translational modifications that are essential for cell function across all domains of life. Changes in... (Review)
Review
Protein glycosylation is one of the most common post-translational modifications that are essential for cell function across all domains of life. Changes in glycosylation are considered a hallmark of many diseases, thus making glycoproteins important diagnostic and prognostic biomarker candidates and therapeutic targets. Glycoproteomics, the study of glycans and their carrier proteins in a system-wide context, is becoming a powerful tool in glycobiology that enables the functional analysis of protein glycosylation. This 'Hitchhiker's guide to glycoproteomics' is intended as a starting point for anyone who wants to explore the emerging world of glycoproteomics. The review moves from the techniques that have been developed for the characterisation of single glycoproteins to technologies that may be used for a successful complex glycoproteome characterisation. Examples of the variety of approaches, methodologies, and technologies currently used in the field are given. This review introduces the common strategies to capture glycoprotein-specific and system-wide glycoproteome data from tissues, body fluids, or cells, and a perspective on how integration into a multi-omics workflow enables a deep identification and characterisation of glycoproteins - a class of biomolecules essential in regulating cell function.
Topics: Glycoproteins; Humans; Proteolysis; Proteomics
PubMed: 34282822
DOI: 10.1042/BST20200879 -
Molecules (Basel, Switzerland) Aug 2022Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively... (Review)
Review
Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.
Topics: Drug Development; Immunotherapy; Neoplasms; Proteolysis
PubMed: 36080223
DOI: 10.3390/molecules27175439 -
Expert Opinion on Drug Discovery Dec 2019: Proteolysis - targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules... (Review)
Review
: Proteolysis - targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. : PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. : PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.
Topics: Animals; Drug Discovery; Humans; Ligands; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 31538491
DOI: 10.1080/17460441.2019.1659242 -
Experimental & Molecular Medicine Oct 2021Proteostasis is primarily a function of protein synthesis and degradation. Although the components and processes involved in intracellular proteostasis have been studied... (Review)
Review
Proteostasis is primarily a function of protein synthesis and degradation. Although the components and processes involved in intracellular proteostasis have been studied extensively, it is apparent that extracellular proteostasis is equitably crucial for the viability of organisms. The 26S proteasome, a unique ATP-dependent proteolytic complex in eukaryotic cells, contributes to the majority of intracellular proteolysis. Accumulating evidence suggests the presence of intact 20S proteasomes in the circulatory system (c-proteasomes), and similar to other plasma proteins, the levels of these c-proteasomes may vary, potentially reflecting specific pathophysiological conditions. Under normal conditions, the concentration of c-proteasomes has been reported to be in the range of ~0.2-2 μg/mL, which is ~2-4-fold lower than that of functional plasma proteins but markedly higher than that of signaling proteins. The characterization of c-proteasomes, such as their origin, structure, role, and clearance, has been delayed mainly due to technical limitations. In this review, we summarize the current perspectives pertaining to c-proteasomes, focusing on the methodology, including our experimental understanding. We believe that once the pathological relevance of c-proteasomes is revealed, these unique components may be utilized in the diagnosis and prognosis of diverse human diseases.
Topics: Eukaryotic Cells; Humans; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 34707192
DOI: 10.1038/s12276-021-00692-x -
Trends in Plant Science Jun 2023Protein homeostasis is epitomized by an equilibrium between protein biosynthesis and degradation: the 'life and death' of proteins. Approximately one-third of newly... (Review)
Review
Protein homeostasis is epitomized by an equilibrium between protein biosynthesis and degradation: the 'life and death' of proteins. Approximately one-third of newly synthesized proteins are degraded. As such, protein turnover is required to maintain cellular integrity and survival. Autophagy and the ubiquitin-proteasome system (UPS) are the two principal degradation pathways in eukaryotes. Both pathways orchestrate many cellular processes during development and upon environmental stimuli. Ubiquitination of degradation targets is used as a 'death' signal by both processes. Recent findings revealed a direct functional link between both pathways. Here, we summarize key findings in the field of protein homeostasis, with an emphasis on the newly revealed crosstalk between both degradation machineries and how it is decided which pathway facilitates target degradation.
Topics: Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin; Ubiquitination; Autophagy
PubMed: 36801193
DOI: 10.1016/j.tplants.2023.01.013 -
Current Genetics Dec 2021Cellular systems depend on multiprotein complexes whose functionalities require defined stoichiometries of subunit proteins. Proper stoichiometry is achieved by... (Review)
Review
Cellular systems depend on multiprotein complexes whose functionalities require defined stoichiometries of subunit proteins. Proper stoichiometry is achieved by controlling the amount of protein synthesis and degradation even in the presence of genetic perturbations caused by changes in gene dosage. As a consequence of increased gene copy number, excess subunits unassembled into the complex are synthesized and rapidly degraded by the ubiquitin-proteasome system. This mechanism, called protein-level dosage compensation, is widely observed not only under such perturbed conditions but also in unperturbed physiological cells. Recent studies have shown that recognition of unassembled subunits and their selective degradation are intricately regulated. This review summarizes the nature, strategies, and increasing complexity of protein-level dosage compensation and discusses possible mechanisms for controlling proteome stoichiometry in multiple layers of biological processes.
Topics: Fungal Proteins; Gene Expression Regulation, Fungal; Models, Biological; Multiprotein Complexes; Protein Binding; Protein Biosynthesis; Proteolysis; Proteome; Yeasts
PubMed: 34382105
DOI: 10.1007/s00294-021-01205-z