-
Angewandte Chemie (International Ed. in... May 2021Proteolysis of proteins and peptides is involved in the infection of cells by enveloped viruses and also in the invasion and spread of cancer cells. Shutting down...
Proteolysis of proteins and peptides is involved in the infection of cells by enveloped viruses and also in the invasion and spread of cancer cells. Shutting down broad-specificity proteases, however, is problematic because normal functions by these proteases will be affected. Herein, nanoparticle receptors were prepared from molecular imprinting for complex biological peptides. Their strong and selective binding enabled them to protect their targeted sequences from proteolysis in aqueous solution at stoichiometric amounts. Generality of the method was demonstrated by the protection of hydrophobic and hydrophilic peptides from different proteases, selective protection of a segment of a long peptide, and selective protection of a targeted peptide in a mixture. Most interestingly, two receptors targeting different parts of a long peptide could work in cooperation to protect the overall sequence, highlighting the versatility of the method.
Topics: Peptide Hydrolases; Peptides; Proteolysis
PubMed: 33725413
DOI: 10.1002/anie.202102148 -
Journal of the American Chemical Society Aug 2023Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically...
Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically active sites, targeted protein degradation is an attractive therapeutic approach. While several methods for targeted protein degradation have been developed, there remains a demand for lower molecular weight molecules that promote efficient degradation of their targets. In this work, we describe the synthesis and validation of a series of heterobifunctional molecules that bind a protein of interest through a small molecule ligand while targeting them to the lysosome using a short gluten peptide that leverages the TG2/LRP-1 pathway. We demonstrate that this approach can be used to effectively endocytose and degrade representative secreted, cell surface, and transmembrane proteins, notably streptavidin, the vitamin B12 receptor, cubilin, and integrin αβ. Optimization of these prototypical molecules could generate pharmacologically relevant LYTAC agents.
Topics: Membrane Proteins; Biological Transport; Proteolysis; Cell Membrane; Lysosomes
PubMed: 37590164
DOI: 10.1021/jacs.3c05109 -
Free Radical Research Dec 2020The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular proteolytic systems that are closely associated with each other. Because UPS and... (Review)
Review
The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular proteolytic systems that are closely associated with each other. Because UPS and autophagy are involved in the clearance of oxidised and/or aggregated proteins, it would be logical to assume that alterations in proteolysis would accompany pathological conditions. Indeed, both systems are themselves susceptible to oxidative modification and therefore could be a prominent target of reactive oxygen species (ROS). Oxidative stress appears to be a common underlying factor in the development of and the pathogenesis of various metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Recent studies, using obesity and hyperglycaemia model mice, reported that both UPS and autophagy systems are inhibited in these mice and that this inhibition is accompanied by lipid accumulation, insulin resistance, and tissue damage. However, the detailed molecular mechanisms that are responsible for regulating intracellular proteolysis in metabolic diseases are not well understood. In the current review, we discuss the correlation between oxidative stress, defective proteolysis, and metabolic diseases. An understanding of how ROS affects intracellular proteolysis may provide new perspectives on the development of and control of diseases.
Topics: Animals; Autophagy; Disease Models, Animal; Humans; Metabolic Diseases; Mice; Oxidative Stress; Proteasome Endopeptidase Complex; Proteolysis
PubMed: 32308060
DOI: 10.1080/10715762.2020.1734588 -
Journal of Medicinal Chemistry Nov 2022The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases.... (Review)
Review
The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the non-enzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation. This perspective aims to specifically summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non-enzymatic functions.
Topics: Humans; Proteolysis; Ubiquitination; Proteins; Signal Transduction
PubMed: 36306471
DOI: 10.1021/acs.jmedchem.2c01159 -
Future Medicinal Chemistry May 2023Targeted protein degradation (TPD) aids in developing novel bifunctional small-molecule degraders and eliminates proteins of interest. The TPD approach shows promising... (Review)
Review
Targeted protein degradation (TPD) aids in developing novel bifunctional small-molecule degraders and eliminates proteins of interest. The TPD approach shows promising results in oncological, neurogenerative, cardiovascular and gynecological drug development. We provide an overview of technology advancements in TPD, including molecular glues, proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras, antibody-based PROTAC, GlueBody PROTAC, autophagy-targeting chimera, autophagosome-tethering compound, autophagy-targeting chimera and chaperone-mediated autophagy-based degraders. Here we discuss the development and evolution of the TPD field, the variety of proteins that PROTACs target and the biological repercussions of their degradation. We particularly highlight the recent improvements in TPD research that utilize autophagy or the endolysosomal pathway, which enables the targeting of undruggable targets.
Topics: Proteolysis; Antibodies; Autophagosomes; Autophagy; Drug Development; Proteolysis Targeting Chimera; Ubiquitin-Protein Ligases
PubMed: 37254917
DOI: 10.4155/fmc-2023-0072 -
Trends in Biochemical Sciences Feb 2023The orchestration of protein production and degradation, and the regulation of protein lifetimes, play a central role in the majority of biological processes. Recent... (Review)
Review
The orchestration of protein production and degradation, and the regulation of protein lifetimes, play a central role in the majority of biological processes. Recent advances in proteomics have enabled the estimation of protein half-lives for thousands of proteins in vivo. What is the utility of these measurements, and how can they be leveraged to interpret the proteome changes occurring during development, aging, and disease? This opinion article summarizes leading technical approaches and highlights their strengths and weaknesses. We also disambiguate frequently used terminology, illustrate recent mechanistic insights, and provide guidance for interpreting and validating protein turnover measurements. Overall, protein lifetimes, coupled to estimates of protein levels, are essential for obtaining a deep understanding of mammalian biology and the basic processes defining life itself.
Topics: Animals; Proteome; Mammals; Proteomics; Proteolysis
PubMed: 36163144
DOI: 10.1016/j.tibs.2022.08.011 -
Annual Review of Pharmacology and... 2016The 26S proteasome is a 2.5-MDa complex, and it operates at the executive end of the ubiquitin-proteasome pathway. It is a proven target for therapeutic agents for the... (Review)
Review
The 26S proteasome is a 2.5-MDa complex, and it operates at the executive end of the ubiquitin-proteasome pathway. It is a proven target for therapeutic agents for the treatment of some cancers and autoimmune diseases, and moreover, it has potential as a target of antibacterial agents. Most inhibitors, including all molecules approved for clinical use, target the 20S proteolytic core complex; its structure was determined two decades ago. Hitherto, efforts to develop inhibitors targeting the 19S regulatory particle subunits have been less successful. This is, in part, because the molecular architecture of this subcomplex has been, until recently, poorly understood, and high-resolution structures have been available only for a few subunits. In this review, we describe, from a structural perspective, the development of inhibitory molecules that target both the 20S and 19S subunits of the proteasome. We highlight the recent progress achieved in structure-based drug-discovery approaches, and we discuss the prospects for further improvement.
Topics: Animals; Drug Discovery; Humans; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis
PubMed: 26738474
DOI: 10.1146/annurev-pharmtox-010814-124727 -
Development (Cambridge, England) Oct 2023Joshua Gendron is Associate Professor of Molecular, Cellular and Developmental Biology at Yale University, USA. His research focuses on understanding how protein...
Joshua Gendron is Associate Professor of Molecular, Cellular and Developmental Biology at Yale University, USA. His research focuses on understanding how protein degradation systems regulate timing mechanisms and environment sensing in plants. Joshua joined the team at Development as a Guest Editor for the journal's Special Issue: Metabolic and Nutritional Control of Development and Regeneration. We met with him over Teams to learn more about why he decided to get involved, his research and his career path.
Topics: Humans; Male; Proteolysis; Research Personnel
PubMed: 37747245
DOI: 10.1242/dev.202268 -
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 -
Bioorganic Chemistry Aug 2022Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been... (Review)
Review
Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.
Topics: Drug Discovery; Ligands; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35533582
DOI: 10.1016/j.bioorg.2022.105848