-
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 -
Drug Discovery Today. Technologies Apr 2019Targeted protein degradation mediated by small molecule degraders represents an exciting new therapeutic opportunity to eliminate disease-causing proteins. These... (Review)
Review
Targeted protein degradation mediated by small molecule degraders represents an exciting new therapeutic opportunity to eliminate disease-causing proteins. These molecules recruit E3 ubiquitin ligases to the protein of interest and mediate its ubiquitination and subsequent proteolysis by the proteasome. Significant advancements have been made in the discovery and development of clinically relevant degraders. In this review we will focus on the recent progress in understanding ternary complex formation and structures, ubiquitination, and other critical factors that govern the efficiency of degraders both in vitro and in vivo. With deeper knowledges of these areas, the field is building guiding principles to reduce the level of empiricism and to identify therapeutically relevant degraders more rationally and efficiently.
Topics: Drug Discovery; Humans; Proteolysis; Ubiquitination
PubMed: 31200860
DOI: 10.1016/j.ddtec.2019.01.001 -
Science Bulletin Jun 2024Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of... (Review)
Review
Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of great clinical significance. According to statistics, over 80% of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods. In recent years, with the advancement of basic research and new technologies, the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets. Among them, targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells. This new form of drug development includes various types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera (AUTAC), autophagy-targeting chimera (AUTOTAC), degrader-antibody conjugate (DAC). This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets. Finally, the article looks forward to the future development direction and application prospects of targeted protein degradation technology.
Topics: Proteolysis; Humans; Autophagy; Proteins; Lysosomes; Drug Development; Molecular Targeted Therapy; Animals
PubMed: 38614856
DOI: 10.1016/j.scib.2024.03.056 -
Nutrients Jan 2020We hypothesized that curcumin may mitigate muscle protein degradation and loss through attenuation of proteolytic activity in limb muscles of mice exposed to reloading...
We hypothesized that curcumin may mitigate muscle protein degradation and loss through attenuation of proteolytic activity in limb muscles of mice exposed to reloading (7dR) following immobilization (7dI). In gastrocnemius of mice (female C57BL/6J, 10 weeks) exposed to recovery following a seven-day period of hindlimb immobilization with/without curcumin treatment, markers of muscle proteolysis (systemic troponin-I), atrophy signaling pathways and histone deacetylases, protein synthesis, and muscle phenotypic characteristics and function were analyzed. In gastrocnemius of reloading mice compared to unloaded, muscle function, structure, sirtuin-1, and protein synthesis improved, while proteolytic and signaling markers (FoxO1/3) declined. In gastrocnemius of unloaded and reloaded mice treated with curcumin, proteolytic and signaling markers (NF-kB p50) decreased and sirtuin-1 activity and hybrid fibers size increased (reloaded muscle), while no significant improvement was seen in muscle function. Treatment with curcumin elicited a rise in sirtuin-1 activity, while attenuating proteolysis in gastrocnemius of mice during reloading following a period of unloading. Curcumin attenuated muscle proteolysis probably via activation of histone deacetylase sirtuin-1, which also led to decreased levels of atrophy signaling pathways. These findings offer an avenue of research in the design of therapeutic strategies in clinical settings of patients exposed to periods of disuse muscle atrophy.
Topics: Animals; Curcumin; Hindlimb Suspension; Muscle, Skeletal; Muscular Atrophy; Phenotype; Proteolysis; Signal Transduction
PubMed: 32024036
DOI: 10.3390/nu12020388 -
The Alkaloids. Chemistry and Biology 2023The 2,5-diketopiperazine (DKP) motif is present in many biologically relevant, complex natural products. The cyclodipeptide substructure offers structural rigidity and... (Review)
Review
The 2,5-diketopiperazine (DKP) motif is present in many biologically relevant, complex natural products. The cyclodipeptide substructure offers structural rigidity and stability to proteolysis that makes these compounds promising candidates for medical applications. Due to their fascinating molecular architecture, synthetic organic chemists have focused significant effort on the total synthesis of these compounds. This review covers many such efforts on the total synthesis of DKP containing complex alkaloid natural products.
Topics: Proteolysis; Diketopiperazines; Alkaloids; Biological Products
PubMed: 37716796
DOI: 10.1016/bs.alkal.2023.06.002 -
Chemical Society Reviews May 2022Targeted protein degradation has emerged from the chemical biology toolbox as one of the most exciting areas for novel therapeutic development across the pharmaceutical... (Review)
Review
Targeted protein degradation has emerged from the chemical biology toolbox as one of the most exciting areas for novel therapeutic development across the pharmaceutical industry. The ability to induce the degradation, and not just inhibition, of target proteins of interest (POIs) with high potency and selectivity is a particularly attractive property for a protein degrader therapeutic. However, the physicochemical properties and mechanism of action for protein degraders can lead to unique pharmacokinetic (PK) and pharmacodynamic (PD) properties relative to traditional small molecule drugs, requiring a shift in perspective for translational pharmacology. In this review, we provide practical insights for building the PK-PD understanding of protein degraders in the context of translational drug development through the use of quantitative mathematical frameworks and standard experimental assays. Published datasets describing protein degrader pharmacology are used to illustrate the applicability of these insights. The learnings are consolidated into a translational PK-PD roadmap for targeted protein degradation that can enable a systematic, rational design workflow for protein degrader therapeutics.
Topics: Models, Biological; Proteolysis
PubMed: 35438107
DOI: 10.1039/d2cs00114d -
Nature Jul 1957
Topics: Collagen; Proteolysis
PubMed: 13451654
DOI: 10.1038/180093a0 -
Food Chemistry Aug 2023Cellular pulse ingredients are increasingly being studied but little knowledge on their proteolysis patterns upon digestion is available. This study investigated a size...
Cellular pulse ingredients are increasingly being studied but little knowledge on their proteolysis patterns upon digestion is available. This study investigated a size exclusion chromatography (SEC) approach to study in vitro protein digestion in chickpea and lentil powders, providing novel insights into proteolysis kinetics and the evolution of molecular weight distributions in the (solubilized) supernatant and (non-solubilized) pellet fractions. For the quantification of proteolysis, SEC-based analysis was compared to the commonly used OPA (o-phthaldialdehyde) approach and nitrogen solubilized upon digestion, leading to highly correlated proteolysis kinetics. Generally, all approaches confirmed that microstructure dictated proteolysis kinetics. However, SEC analysis delivered an additional level of molecular insight. For the first time, SEC revealed that while bioaccessible fractions reached a plateau in the small intestinal phase (around 45-60 min), proteolysis continued in the pellet, forming smaller but mostly insoluble peptides. SEC elutograms showed pulse-specific proteolysis patterns, unidentified using other current state-of-the-art methods.
Topics: Proteolysis; Powders; Digestion; Peptides; Chromatography, Gel
PubMed: 37023667
DOI: 10.1016/j.foodchem.2023.135709 -
Nature Reviews. Drug Discovery Oct 2022
Topics: Humans; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 36056259
DOI: 10.1038/d41573-022-00152-9 -
European Journal of Medicinal Chemistry Dec 2023Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.
Topics: Proteolysis Targeting Chimera; Chemistry, Pharmaceutical; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37708797
DOI: 10.1016/j.ejmech.2023.115793