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Future Medicinal Chemistry Apr 2022
Topics: Antiviral Agents; Proteolysis; Ubiquitination
PubMed: 35134309
DOI: 10.4155/fmc-2022-0005 -
Expert Opinion on Drug Discovery Apr 2023Target protein degradation (TPD) provides a novel therapeutic modality, other than inhibition, through the direct depletion of target proteins. Two primary human protein... (Review)
Review
INTRODUCTION
Target protein degradation (TPD) provides a novel therapeutic modality, other than inhibition, through the direct depletion of target proteins. Two primary human protein homeostasis mechanisms are exploited: the ubiquitin-proteasome system (UPS) and the lysosomal system. TPD technologies based on these two systems are progressing at an impressive pace.
AREAS COVERED
This review focuses on the TPD strategies based on UPS and lysosomal system, mainly classified into three types: Molecular Glue (MG), PROteolysis Targeting Chimera (PROTAC), and lysosome-mediated TPD. Starting with a brief background introduction of each strategy, exciting examples and perspectives on these novel approaches are provided.
EXPERT OPINION
MGs and PROTACs are two major UPS-based TPD strategies that have been extensively investigated in the past decade. Despite some clinical trials, several critical issues remain, among which is emphasized by the limitation of targets. Recently developed lysosomal system-based approaches provide alternative solutions for TPD beyond UPS' capability. The newly emerging novel approaches may partially address issues that have long plagued researchers, such as low potency, poor cell permeability, on-/off-target toxicity, and delivery efficiency. Comprehensive considerations for the rational design of protein degraders and continuous efforts to seek effective solutions are imperative to advance these strategies into clinical medications.
Topics: Humans; Proteolysis; Drug Discovery; Permeability; Proteolysis Targeting Chimera; Research Personnel
PubMed: 36895136
DOI: 10.1080/17460441.2023.2187777 -
Cell Chemical Biology Jul 2021
Topics: Humans; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 34270936
DOI: 10.1016/j.chembiol.2021.06.011 -
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 -
Molecules (Basel, Switzerland) Aug 2021Proteases play a central role in various biochemical pathways catalyzing and regulating key biological events. Proteases catalyze an irreversible post-translational... (Review)
Review
Proteases play a central role in various biochemical pathways catalyzing and regulating key biological events. Proteases catalyze an irreversible post-translational modification called proteolysis by hydrolyzing peptide bonds in proteins. Given the destructive potential of proteolysis, protease activity is tightly regulated. Dysregulation of protease activity has been reported in numerous disease conditions, including cancers, neurodegenerative diseases, inflammatory conditions, cardiovascular diseases, and viral infections. The proteolytic profile of a cell, tissue, or organ is governed by protease activation, activity, and substrate specificity. Thus, identifying protease substrates and proteolytic events under physiological conditions can provide crucial information about how the change in protease regulation can alter the cellular proteolytic landscape. In recent years, mass spectrometry-based techniques called N-terminomics have become instrumental in identifying protease substrates from complex biological mixtures. N-terminomics employs the labeling and enrichment of native and neo-N-termini peptides, generated upon proteolysis followed by mass spectrometry analysis allowing protease substrate profiling directly from biological samples. In this review, we provide a brief overview of N-terminomics techniques, focusing on their strengths, weaknesses, limitations, and providing specific examples where they were successfully employed to identify protease substrates in vivo and under physiological conditions. In addition, we explore the current trends in the protease field and the potential for future developments.
Topics: Humans; Mass Spectrometry; Peptide Hydrolases; Peptides; Proteolysis; Proteomics; Substrate Specificity
PubMed: 34361849
DOI: 10.3390/molecules26154699 -
Current Opinion in Chemical Biology Aug 2020Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules and allow selective protein degradation by addressing the natural ubiquitin proteasome system.... (Review)
Review
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules and allow selective protein degradation by addressing the natural ubiquitin proteasome system. As this new strategy of chemically induced protein degradation can serve as a biological tool and provides new possibilities for drug discovery, it has been applied to a variety of targets including (nuclear) receptors, kinases, and epigenetic proteins. A lot of PROTACs have already been designed in the field of epigenetics, and their synthesis and characterization highly contributed to structural optimization and improved mechanistic understanding of these molecules. In this review, we will discuss and summarize recent advances in PROTAC discovery with focus on epigenetic targets.
Topics: Animals; Drug Discovery; Epigenesis, Genetic; Epigenomics; Humans; Models, Molecular; Molecular Targeted Therapy; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin
PubMed: 32146413
DOI: 10.1016/j.cbpa.2020.01.010 -
Sub-cellular Biochemistry 2019Proteasomes are a class of protease that carry out the degradation of a specific set of cellular proteins. While essential for eukaryotic life, proteasomes are found... (Review)
Review
Proteasomes are a class of protease that carry out the degradation of a specific set of cellular proteins. While essential for eukaryotic life, proteasomes are found only in a small subset of bacterial species. In this chapter, we present the current knowledge of bacterial proteasomes, detailing the structural features and catalytic activities required to achieve proteasomal proteolysis. We describe the known mechanisms by which substrates are doomed for degradation, and highlight potential non-degradative roles for components of bacterial proteasome systems. Additionally, we highlight several pathways of microbial physiology that rely on proteasome activity. Lastly, we explain the various gaps in our understanding of bacterial proteasome function and emphasize several opportunities for further study.
Topics: Bacteria; Bacterial Proteins; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 31939157
DOI: 10.1007/978-3-030-28151-9_11 -
Chemical Society Reviews Nov 2022Proteolysis-targeting chimeras (PROTACs) and targeted covalent inhibitors (TCIs) are currently two exciting strategies in the fields of chemical biology and drug... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) and targeted covalent inhibitors (TCIs) are currently two exciting strategies in the fields of chemical biology and drug discovery. Extensive research in these two fields has been conducted, and significant progress in these fields has resulted in many clinical candidates, some of which have been approved by FDA. Recently, a novel concept termed covalent PROTACs that combine these two strategies has emerged and gained an increasing interest in the past several years. Herein, we briefly review and highlight the mechanism and advantages of TCIs and PROTACs, respectively, and the recent development of covalent PROTACs using irreversible and reversible covalent chemistry.
Topics: Proteolysis; Ubiquitin-Protein Ligases; Drug Discovery
PubMed: 36285735
DOI: 10.1039/d2cs00362g -
Journal of Enzyme Inhibition and... Dec 2022Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic... (Review)
Review
Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ∼70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed.
Topics: Intercellular Signaling Peptides and Proteins; Ligands; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35702041
DOI: 10.1080/14756366.2022.2076675 -
BioEssays : News and Reviews in... Jan 2015We propose for the first time to divide histone proteolysis into "histone degradation" and the epigenetically connoted "histone clipping". Our initial observation is... (Review)
Review
We propose for the first time to divide histone proteolysis into "histone degradation" and the epigenetically connoted "histone clipping". Our initial observation is that these two different classes are very hard to distinguish both experimentally and biologically, because they can both be mediated by the same enzymes. Since the first report decades ago, proteolysis has been found in a broad spectrum of eukaryotic organisms. However, the authors often not clearly distinguish or determine whether degradation or clipping was studied. Given the importance of histone modifications in epigenetic regulation we further elaborate on the different ways in which histone proteolysis could play a role in epigenetics. Finally, unanticipated histone proteolysis has probably left a mark on many studies of histones in the past. In conclusion, we emphasize the significance of reviving the study of histone proteolysis both from a biological and an experimental perspective. Also watch the Video Abstract.
Topics: Animals; Histones; Humans; Models, Biological; Proteolysis
PubMed: 25350939
DOI: 10.1002/bies.201400118