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Gene Aug 2023Ubiquitination is a widespread post-transcriptional modification (PTM) that occurs during protein degradation in eukaryotes and participates in almost all physiological... (Review)
Review
Ubiquitination is a widespread post-transcriptional modification (PTM) that occurs during protein degradation in eukaryotes and participates in almost all physiological and pathological processes, including animal adipogenesis. Ubiquitination is a cascade reaction regulated by the activating enzyme E1, conjugating enzyme E2, and ligase E3. Several recent studies have reported that E3 ligases play important regulatory roles in adipogenesis. However, as a key influencing factor for the recognition and connection between the substrate and ubiquitin during ubiquitination, its regulatory role in adipogenesis has not received adequate attention. In this review, we summarize the E3s' regulation and modification targets in animal adipogenesis, explain the regulatory mechanisms in lipogenic-related pathways, and further analyze the existing positive results to provide research directions of guiding significance for further studies on the regulatory mechanisms of E3s in animal adipogenesis.
Topics: Animals; Adipogenesis; Ubiquitination; Ubiquitin-Protein Ligases; Ubiquitin; Proteolysis; Ubiquitin-Conjugating Enzymes
PubMed: 37336271
DOI: 10.1016/j.gene.2023.147574 -
Angewandte Chemie (International Ed. in... Jan 2024Proteolysis targeting chimera (PROTAC) is a state-of-the-art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD)... (Review)
Review
Proteolysis targeting chimera (PROTAC) is a state-of-the-art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril-based PROTAC strategy to form a polynary (E3) : PROTAC : (POI) complex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self-assembly-driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so-called Nano-PROTAC provides a novel approach for TPD in cancer therapy.
Topics: Proteolysis; Ligands; Ubiquitin-Protein Ligases; Peptides
PubMed: 38059785
DOI: 10.1002/anie.202316581 -
Journal of Medicinal Chemistry Nov 2023Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera...
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.
Topics: Proteolysis; Proteolysis Targeting Chimera; Ubiquitin-Protein Ligases; Ligands; Nuclear Proteins; Transcription Factors; Adaptor Proteins, Signal Transducing
PubMed: 37902300
DOI: 10.1021/acs.jmedchem.3c00851 -
Journal of Medicinal Chemistry Aug 2023Targeted protein degradation (TPD) technologies have catalyzed a paradigm shift in therapeutic strategies and offer innovative avenues for drug design. Hydrophobic tags... (Review)
Review
Targeted protein degradation (TPD) technologies have catalyzed a paradigm shift in therapeutic strategies and offer innovative avenues for drug design. Hydrophobic tags (HyTs) are bifunctional TPD molecules consisting of a ″lipophilic small-molecule tags″ group and a small-molecule ligand for the target protein. Despite the vast potential of HyTs, they have received relatively limited attention as a promising frontier. Leveraging their lower molecular weight and reduced numbers of hydrogen bond donors/acceptors (HBDs/HBAs) in comparison with proteolysis-targeting chimeras (PROTACs), HyTs present a compelling approach for enhancing druglike properties. In this Perspective, we explore the diverse range of HyT structures and their corresponding degradation mechanisms, thereby illuminating their broad applicability in targeting a diverse array of proteins, including previously elusive targets. Moreover, we scrutinize the challenges and opportunities entailed in developing this technology as a viable and fruitful strategy for drug discovery.
Topics: Proteolysis; Proteins; Drug Discovery; Drug Design; Ubiquitination; Ubiquitin-Protein Ligases; Proteasome Endopeptidase Complex
PubMed: 37535706
DOI: 10.1021/acs.jmedchem.3c00736 -
Journal of Medicinal Chemistry Jul 2023Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal... (Review)
Review
Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal chemists. Molecules with such modes of action have a large potential not only as drugs but also as chemical probes. Criteria have previously been established to describe the potency, selectivity, and properties of small-molecule probes that are qualified to enable the interrogation and validation of drug targets. These definitions have been tailored to reversibly acting modulators but fall short in their applicability to other modalities. While initial guidelines have been proposed, we delineate here a full set of criteria for the characterization of covalent, irreversible inhibitors as well as heterobifunctional degraders ("proteolysis-targeting chimeras", or PROTACs) and molecular glue degraders. We propose modified potency and selectivity criteria compared to those for reversible inhibitors. We discuss their relevance and highlight examples of suitable probe and pathfinder compounds.
Topics: Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37403870
DOI: 10.1021/acs.jmedchem.3c00550 -
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 -
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 -
Cellular and Molecular Life Sciences :... Jul 2023The human chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is involved in several homeostatic processes and pathologies through interaction with its cognate G...
The human chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is involved in several homeostatic processes and pathologies through interaction with its cognate G protein-coupled receptor CXCR4. Recent research has shown that CXCL12 is present in the lungs and circulation of patients with coronavirus disease 2019 (COVID-19). However, the question whether the detected CXCL12 is bioactive was not addressed. Indeed, the activity of CXCL12 is regulated by NH- and COOH-terminal post-translational proteolysis, which significantly impairs its biological activity. The aim of the present study was to characterize proteolytic processing of CXCL12 in broncho-alveolar lavage (BAL) fluid and blood plasma samples from critically ill COVID-19 patients. Therefore, we optimized immunosorbent tandem mass spectrometry proteoform analysis (ISTAMPA) for detection of CXCL12 proteoforms. In patient samples, this approach uncovered that CXCL12 is rapidly processed by site-specific NH- and COOH-terminal proteolysis and ultimately degraded. This proteolytic inactivation occurred more rapidly in COVID-19 plasma than in COVID-19 BAL fluids, whereas BAL fluid samples from stable lung transplantation patients and the non-affected lung of lung cancer patients (control groups) hardly induced any processing of CXCL12. In COVID-19 BAL fluids with high proteolytic activity, processing occurred exclusively NH-terminally and was predominantly mediated by neutrophil elastase. In low proteolytic activity BAL fluid and plasma samples, NH- and COOH-terminal proteolysis by CD26 and carboxypeptidases were observed. Finally, protease inhibitors already approved for clinical use such as sitagliptin and sivelestat prevented CXCL12 processing and may therefore be of pharmacological interest to prolong CXCL12 half-life and biological activity in vivo.
Topics: Humans; Proteolysis; COVID-19; Chemokine CXCL12; Peptide Hydrolases; Lung; Receptors, CXCR4; Protein Processing, Post-Translational
PubMed: 37505242
DOI: 10.1007/s00018-023-04870-0 -
Nature Biotechnology Apr 2024
Topics: Biodegradation, Environmental; Proteolysis
PubMed: 38448663
DOI: 10.1038/s41587-024-02164-9 -
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