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Chemical Society Reviews Apr 2024Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and... (Review)
Review
Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and clinical contexts. The unique TPD mode-of-action has allowed previously undruggable proteins to become feasible targets, expanding the landscape of "druggable" properties and "privileged" target proteins. As TPD continues to evolve, a range of innovative strategies, which do not depend on recruiting E3 ubiquitin ligases as in proteolysis-targeting chimeras (PROTACs), have emerged. Here, we present an overview of direct lysosome- and proteasome-engaging modalities and discuss their perspectives, advantages, and limitations. We outline the chemical composition, biochemical activity, and pharmaceutical characteristics of each degrader. These alternative TPD approaches not only complement the first generation of PROTACs for intracellular protein degradation but also offer unique strategies for targeting pathologic proteins located on the cell membrane and in the extracellular space.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Lysosomes; Cell Membrane; Ubiquitin-Protein Ligases
PubMed: 38369971
DOI: 10.1039/d3cs00344b -
Biological Chemistry Nov 2018
Topics: Humans; Proteolysis; Proteomics
PubMed: 30352023
DOI: 10.1515/hsz-2018-0401 -
Trends in Neurosciences Aug 2014Activity-controlled enzymatic cleavage of proteins on the surface of synaptic membranes or in the synaptic or perisynaptic interstitial compartment represents a direct... (Review)
Review
Activity-controlled enzymatic cleavage of proteins on the surface of synaptic membranes or in the synaptic or perisynaptic interstitial compartment represents a direct way to regulate synaptic structure, function, and number. Extracellular proteolysis at synapses was initially understood to be plasticity enabling by freeing synapses from the constraints provided by the extracellular matrix. However, recent observations indicate that at least part of the extracellular protein cleavage results in activation of previously cryptic functions that regulate adaptive changes of synapses and neuronal circuits. Here, we focus on peptidases with distinct localization and function at synapses combined with regulation by neuronal and synaptic activity, and evaluate their function in the context of developmental and/or adult synaptic plasticity.
Topics: Animals; Extracellular Matrix; Humans; Nerve Net; Peptide Hydrolases; Proteolysis; Synapses
PubMed: 24969462
DOI: 10.1016/j.tins.2014.05.007 -
European Journal of Medicinal Chemistry Nov 2023Targeted protein degradation (TPD) has emerged as a promising approach for drug development, particularly for undruggable targets. TPD technology has also been... (Review)
Review
Targeted protein degradation (TPD) has emerged as a promising approach for drug development, particularly for undruggable targets. TPD technology has also been instrumental in overcoming drug resistance. While some TPD molecules utilizing proteolysis-targeting chimera (PROTACs) or molecular glue strategies have been approved or evaluated in clinical trials, hydrophobic tag-based protein degradation (HyT-PD) has also gained significant attention as a tool for medicinal chemists. The increasing number of reported HyT-PD molecules possessing high efficiency in degrading protein and good pharmacokinetic (PK) properties, has further fueled interest in this approach. This review aims to present the design rationale, hydrophobic tags in use, and diverse mechanisms of action of HyT-PD. Additionally, the advantages and disadvantages of HyT-PD in protein degradation are discussed. This review may help inspire the development of more HyT-PDs with superior drug-like properties for clinical evaluation.
Topics: Humans; Proteolysis; Drug Development; Proteolysis Targeting Chimera; Skin Neoplasms; Technology
PubMed: 37607438
DOI: 10.1016/j.ejmech.2023.115741 -
Biomolecules Nov 2021The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome... (Review)
Review
The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases. In this review, we discuss the structure of proteasome and how proteasome's proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.
Topics: Aging; Humans; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Folding; Proteolysis; Small Molecule Libraries
PubMed: 34944433
DOI: 10.3390/biom11121789 -
Nature Biotechnology Apr 2024
Topics: Biodegradation, Environmental; Proteolysis
PubMed: 38448663
DOI: 10.1038/s41587-024-02164-9 -
The FEBS Journal May 2020Proteases play critical roles in virtually all biological processes, including proliferation, cell death and survival, protein turnover, and migration. However, when... (Review)
Review
Proteases play critical roles in virtually all biological processes, including proliferation, cell death and survival, protein turnover, and migration. However, when dysregulated, these enzymes contribute to the progression of multiple diseases, with cancer, neurodegenerative disorders, inflammation, and blood disorders being the most prominent examples. For a long time, disease-associated proteases have been used for the activation of various prodrugs due to their well-characterized catalytic activity and ability to selectively cleave only those substrates that strictly correspond with their active site architecture. To date, versatile peptide sequences that are cleaved by proteases in a site-specific manner have been utilized as bioactive linkers for the targeted delivery of multiple types of cargo, including fluorescent dyes, photosensitizers, cytotoxic drugs, antibiotics, and pro-antibodies. This platform is highly adaptive, as multiple protease-labile conjugates have already been developed, some of which are currently in clinical use for cancer treatment. In this review, recent advancements in the development of novel protease-cleavable linkers for selective drug delivery are described. Moreover, the current limitations regarding the selectivity of linkers are discussed, and the future perspectives that rely on the application of unnatural amino acids for the development of highly selective peptide linkers are also presented.
Topics: Catalysis; Catalytic Domain; Drug Delivery Systems; Humans; Peptide Hydrolases; Peptides; Prodrugs; Proteolysis
PubMed: 31991521
DOI: 10.1111/febs.15227 -
Advances in Experimental Medicine and... 2019Enzymes are biocatalysts that have found profound applications in the current biotherapeutic industry and play a crucial role in diagnosis, prevention, and biochemical... (Review)
Review
Enzymes are biocatalysts that have found profound applications in the current biotherapeutic industry and play a crucial role in diagnosis, prevention, and biochemical analysis of major diseases. However, stability, protein degradation and immunogenicity in the body present unique challenges that are faced upon sustained use of such enzymes. The present chapter is an attempt to dissect the state-of-the-art in relation to the challenges of development of therapeutic enzymes and the recent advances to address them. At the very outset, diseases where enzymes have found effective applications and the various causes of enzyme instability have been discussed. In recent times, polymer or nano- conjugated resistant delivery methods, as well as mutagenesis have led to manifold increase in enzyme stability against thermal denaturation, acidic gut environment, proteolysis and immunogenicity. Further, methods of analytical characterization of proteins have been highlighted and explored to shape future research directions.
Topics: Enzyme Stability; Enzymes; Proteolysis
PubMed: 31482498
DOI: 10.1007/978-981-13-7709-9_7 -
European Journal of Medicinal Chemistry Feb 2024Proteolysis-targeting chimaera (PROTAC) technology functions by directly targeting proteins and catalysing their degradation through an event-driven mode of action, a... (Review)
Review
Proteolysis-targeting chimaera (PROTAC) technology functions by directly targeting proteins and catalysing their degradation through an event-driven mode of action, a novel mechanism with significant clinical application prospects for various diseases. Currently, the most advanced PROTAC drug is undergoing phase III clinical trials (NCT05654623). Although PROTACs exhibit significant advantages over traditional small-molecule inhibitors, their catalytic degradation of normal cellular proteins can potentially cause toxic side effects. Therefore, to achieve targeted release of PROTACs and minimize adverse reactions, researchers are actively exploring diverse controllable PROTACs. In this review, we comprehensively summarize the control strategies to provide a theoretical basis for the innovative application of PROTAC technology.
Topics: Catalysis; Proteolysis; Technology; Ubiquitin-Protein Ligases; Proteolysis Targeting Chimera
PubMed: 38160619
DOI: 10.1016/j.ejmech.2023.116096 -
Anti-cancer Agents in Medicinal... 2022Breast Cancer (BC) is the most widely occurring disease in women. A massive number of women are diagnosed with breast cancer, and many lose their lives every year.... (Review)
Review
BACKGROUND
Breast Cancer (BC) is the most widely occurring disease in women. A massive number of women are diagnosed with breast cancer, and many lose their lives every year. Cancer is the leading cause of death worldwide, posing a formidable challenge to the current medication difficulties.
OBJECTIVES
The main objective of this study is to examine and explore novel therapy (PROTAC) and its effectiveness against breast cancer.
METHODS
The literature search was conducted across Medline, Cochrane, ScienceDirect, Wiley Online, Google Scholar, PubMed, and Bentham Sciences from 2001 to 2020. The articles collected were screened, segregated, and selected papers were included for writing the review article.
RESULTS AND CONCLUSION
A novel innovation emerged around two decades ago that has great potential to overcome the limitations and provide future direction for the treatment of many diseases, which has presently not many therapeutic options available and are regarded as incurable with traditional techniques. That innovation is called PROTAC (Proteolysis Targeting Chimera), which can efficaciously ubiquitinate and debase cancer, encouraging proteins through noncovalent interaction. PROTACs constituted of two active regions isolated by a linker are equipped for eliminating explicit undesirable protein. It is empowering greater sensitivity to "drugresistant targets" and a more prominent opportunity to influence non-enzymatic function. PROTACs have been demonstrated to show better target selectivity contrasted with traditional small-molecule inhibitors. So far, the most investigation into PROTACs mainly concentrated on cancer treatment applications, including breast cancer. The treatment of different ailments may benefit the patients from this blossoming innovation.
Topics: Antineoplastic Agents; Breast Neoplasms; Female; Humans; Proteolysis; Small Molecule Libraries
PubMed: 33687888
DOI: 10.2174/1871520621666210308100327