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Journal of Experimental & Clinical... Sep 2020Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of... (Review)
Review
Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional structures consisting of a ligand that binds a protein to be degraded and a ligand for an E3 ubiquitin ligase. The bridging between the protein of interest and the E3 ligase mediated by the PROTAC facilitates ubiquitination of the protein and its proteasomal degradation. In this review we discuss the molecular medicine behind PROTAC mechanism of action, with special emphasis on recent developments and their potential translation to the clinical setting.
Topics: Animals; Antineoplastic Agents; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Proteolysis; Ubiquitination
PubMed: 32933565
DOI: 10.1186/s13046-020-01672-1 -
International Journal of Biological... 2023Targeted therapies in cancer treatment can improve efficacy and reduce adverse effects by altering the tissue exposure of specific biomolecules. However, there are... (Review)
Review
Targeted therapies in cancer treatment can improve efficacy and reduce adverse effects by altering the tissue exposure of specific biomolecules. However, there are still large number of target proteins in cancer are still undruggable, owing to the following factors including (1) lack of ligand-binding pockets, (2) function based on protein-protein interactions (PPIs), (3) the highly specific conserved active sites among protein family members, and (4) the variability of tertiary docking structures. The current status of undruggable targets proteins such as KRAS, TP53, C-MYC, PTP, are carefully introduced in this review. Some novel techniques and drug designing strategies have been applicated for overcoming these undruggable proteins, and the most classic and well-known technology is proteolysis targeting chimeras (PROTACs). In this review, the novel drug development strategies including targeting protein degradation, targeting PPI, targeting intrinsically disordered regions, as well as targeting protein-DNA binding are described, and we also discuss the potential of these strategies for overcoming the undruggable targets. Besides, intelligence-assisted technologies like Alpha-Fold help us a lot to predict the protein structure, which is beneficial for drug development. The discovery of new targets and the development of drugs targeting them, especially those undruggable targets, remain a huge challenge. New drug development strategies, better extraction processes that do not disrupt protein-protein interactions, and more precise artificial intelligence technologies may provide significant assistance in overcoming these undruggable targets.
Topics: Humans; Artificial Intelligence; Proteins; Proteolysis; Neoplasms; Drug Discovery
PubMed: 37496997
DOI: 10.7150/ijbs.83026 -
International Journal of Biological... 2023Gasdermins (GSDMs) serve as pivotal executors of pyroptosis and play crucial roles in host defence, cytokine secretion, innate immunity, and cancer. However, excessive... (Review)
Review
Gasdermins (GSDMs) serve as pivotal executors of pyroptosis and play crucial roles in host defence, cytokine secretion, innate immunity, and cancer. However, excessive or inappropriate GSDMs activation is invariably accompanied by exaggerated inflammation and results in tissue damage. In contrast, deficient or impaired activation of GSDMs often fails to promptly eliminate pathogens, leading to the increasing severity of infections. The activity of GSDMs requires meticulous regulation. The dynamic modulation of GSDMs involves many aspects, including autoinhibitory structures, proteolytic cleavage, lipid binding and membrane translocation (oligomerization and pre-pore formation), oligomerization (pore formation) and pore removal for membrane repair. As the most comprehensive and efficient regulatory pathway, posttranslational modifications (PTMs) are widely implicated in the regulation of these aspects. In this comprehensive review, we delve into the complex mechanisms through which a variety of proteases cleave GSDMs to enhance or hinder their function. Moreover, we summarize the intricate regulatory mechanisms of PTMs that govern GSDMs-induced pyroptosis.
Topics: Gasdermins; Protein Processing, Post-Translational; Proteolysis; Endopeptidases; Immunity, Innate; Peptide Hydrolases
PubMed: 37781519
DOI: 10.7150/ijbs.86869 -
Seminars in Cancer Biology Nov 2022Tumor microenvironment (TME) composes of multiple cell types and non-cellular components, which supports the proliferation, metastasis and immune surveillance evasion of... (Review)
Review
Tumor microenvironment (TME) composes of multiple cell types and non-cellular components, which supports the proliferation, metastasis and immune surveillance evasion of tumor cells, as well as accounts for the resistance to therapies. Therefore, therapeutic strategies using small molecule inhibitors (SMIs) and antibodies to block potential targets in TME are practical for cancer treatment. Targeted protein degradation using PROteolysis-TArgeting Chimera (PROTAC) technic has several advantages over traditional SMIs and antibodies, including overcoming drug resistance. Thus many PROTACs are currently under development for cancer treatment. In this review, we summarize the recent progress of PROTAC development that target TME pathways and propose the potential direction of future PROTAC technique to advance as novel cancer treatment options.
Topics: Humans; Drug Discovery; Proteolysis; Neoplasms; Ubiquitin-Protein Ligases; Tumor Microenvironment
PubMed: 35798235
DOI: 10.1016/j.semcancer.2022.07.001 -
Journal of the American Chemical Society Apr 2024Disruption of protein-protein interactions is medicinally important. Interface helices may be mimicked in helical probes featuring enhanced rigidities, binding to...
Disruption of protein-protein interactions is medicinally important. Interface helices may be mimicked in helical probes featuring enhanced rigidities, binding to protein targets, stabilities in serum, and cell uptake. This form of mimicry is dominated by stapling between side chains of helical residues: there has been less progress on helical -caps, and there were no generalizable -caps. Conversely, in natural proteins, helicities are stabilized and terminated by - and caps but not staples. Bicyclic caps previously introduced by us enable interface helical mimicry featuring rigid synthetic caps at both termini in this work. An unambiguously helical dual-capped system proved to be conformationally stable, binding cyclins A and E, and showed impressive cellular uptake. In addition, the dual-capped mimic was completely resistant to proteolysis in serum over an extended period when compared with "gold standard" hydrocarbon-stapled controls. Dual-capped peptidomimetics are a new, generalizable paradigm for helical interface probe design.
Topics: Peptides; Protein Structure, Secondary; Proteolysis
PubMed: 38573124
DOI: 10.1021/jacs.3c11717 -
International Journal of Molecular... Jan 2019The mortality rates of cancer patients decreased by ~1.5% per year between 2001 and 2015, although the decrease depends on patient sex, ethnic group and type of... (Review)
Review
The mortality rates of cancer patients decreased by ~1.5% per year between 2001 and 2015, although the decrease depends on patient sex, ethnic group and type of malignancy. Cancer remains a significant global health problem, requiring a search for novel treatments. The most common property of malignant tumors is their capacity to invade adjacent tissue and to metastasize, and this cancer aggressiveness is contingent on overexpression of proteolytic enzymes. The components of the plasminogen activation system (PAS) and the metalloproteinase family [mainly matrix metalloproteinases (MMPs)] are overexpressed in malignant tumors, driving the local invasion, metastasis and angiogenesis. This is the case for numerous types of cancer, such as breast, colon, prostate and oral carcinoma, among others. Present chemotherapeutics agents typically attack all dividing cells; however, for future therapeutic agents to be clinically successful, they need to be highly selective for a specific protein(s) and act on the cancerous tissues without adverse systemic effects. Inhibition of proteolysis in cancerous tissue has the ability to attenuate tumor invasion, angiogenesis and migration. For that purpose, inhibiting both PAS and MMPs may be another approach, since the two groups of enzymes are overexpressed in cancer. In the present review, the roles and new findings on PAS and MMP families in cancer formation, growth and possible treatments are discussed.
Topics: Animals; Humans; Neoplasms; Neovascularization, Pathologic; Peptide Hydrolases; Protease Inhibitors; Proteolysis
PubMed: 30431071
DOI: 10.3892/ijmm.2018.3983 -
Chembiochem : a European Journal of... Sep 2022Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker...
Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker connecting the E3 Ubiquitin Ligase (E3 Ubl) and target protein (TP) ligands, which therefore requires tedious optimization. The creation of "split PROTACs" from E3 Ubl and TP ligands modified with residues suitable for them to couple when simply mixed together would allow various combinations to be assessed in a combinatorial fashion, thus greatly easing the workload relative to a one-by-one synthesis of many different PROTACs (proteolysis targeting chimeras). We explore oxime chemistry here for this purpose. We show that PROTAC assembly occurs efficiently when the components are mixed at a high concentration, then added to cells. However, in situ coupling of the TP and E3 Ubl ligands is inefficient when these units are added to cells at lower concentrations.
Topics: Ligands; Oximes; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35802347
DOI: 10.1002/cbic.202200275 -
Developmental Neurobiology Mar 2018Membrane protein turnover and degradation are required for the function and health of all cells. Neurons may live for the entire lifetime of an organism and are highly... (Review)
Review
Membrane protein turnover and degradation are required for the function and health of all cells. Neurons may live for the entire lifetime of an organism and are highly polarized cells with spatially segregated axonal and dendritic compartments. Both longevity and morphological complexity represent challenges for regulated membrane protein degradation. To investigate how neurons cope with these challenges, an increasing number of recent studies investigated local, cargo-specific protein sorting, and degradation at axon terminals and in dendritic processes. In this review, we explore the current answers to the ensuing questions of where, what, and when membrane proteins are degraded in neurons. © 2017 The Authors Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 283-297, 2018.
Topics: Animals; Humans; Membrane Proteins; Neurons; Proteolysis
PubMed: 28884504
DOI: 10.1002/dneu.22534 -
Translational Research : the Journal of... Jun 2020The current tuberculosis (TB) predicament poses numerous challenges and therefore every incremental scientific work and all positive socio-political engagements, are... (Review)
Review
The current tuberculosis (TB) predicament poses numerous challenges and therefore every incremental scientific work and all positive socio-political engagements, are steps taken in the right direction to eradicate TB. Progression of the late stage TB-drug pipeline into the clinics is an immediate deliverable of this global effort. At the same time, fueling basic research and pursuing early discovery work must be sustained to maintain a healthy TB-drug pipeline. This review encompasses a broad analysis of chemotherapeutic strategies that target the DNA replication, protein synthesis, cell wall biosynthesis, energy metabolism and proteolysis of Mycobacterium tuberculosis (Mtb). It includes a status check of the current TB-drug pipeline with a focus on the associated biology, emerging targets, and their promising chemical inhibitors. Potential synergies and/or gaps within or across different chemotherapeutic strategies are systematically reviewed as well.
Topics: Antitubercular Agents; Cell Wall; DNA Replication; Energy Metabolism; Mycolic Acids; Protein Synthesis Inhibitors; Proteolysis
PubMed: 32275897
DOI: 10.1016/j.trsl.2020.03.007 -
Angewandte Chemie (International Ed. in... Sep 2020Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created... (Review)
Review
Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created tremendous excitement in chemical biology and drug discovery within the past decades. The TPD field is spearheaded by small molecule induced protein degradation with molecular glues and proteolysis targeting chimeras (PROTACs) paving the way to expand the druggable space and to create a new paradigm in drug discovery. However, besides the therapeutic angle of TPD a plethora of novel techniques to modulate and control protein levels have been developed. This enables chemical biologists to better understand protein function and to discover and verify new therapeutic targets. This Review gives a comprehensive overview of chemical biology techniques inducing TPD. It explains the strengths and weaknesses of these methods in the context of drug discovery and discusses their future potential from a medicinal chemist's perspective.
Topics: Humans; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 32428344
DOI: 10.1002/anie.202004310