Targeted protein degradation: mechanisms, strategies and application

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Апрель 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Язык: Английский

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Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 2, 2023

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets

Язык: Английский

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The RING finger protein family in health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Авг. 30, 2022

Ubiquitination is a highly conserved and fundamental posttranslational modification (PTM) in all eukaryotes regulating thousands of proteins. The RING (really interesting new gene) finger (RNF) protein, containing the domain, exerts E3 ubiquitin ligase that mediates covalent attachment (Ub) to target Multiple reviews have summarized critical roles tripartite-motif (TRIM) protein family, subgroup RNF proteins, various diseases, including cancer, inflammatory, infectious, neuropsychiatric disorders. Except for TRIMs, since numerous studies over past decades delineated other proteins also exert widespread involvement several their importance should not be underestimated. This review summarizes potential contribution dysregulated except pathogenesis some autoimmune neurodegenerative disorder. Since viral infection broadly involved induction development those this manuscript highlights regulatory excluding antiviral immune responses. In addition, we further discuss intervention strategies targeting prevention therapeutics human diseases.

Язык: Английский

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Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Май 27, 2023

The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. most common form NCD is metabolic diseases, which affect people all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding the will generate novel targets for improved therapies across spectrum. Protein posttranslational modification (PTM) an important term that refers to biochemical specific amino acid residues in target proteins, immensely increases functional diversity proteome. range PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, several PTMs. Here, we offer review roles pathological consequences, including diabetes, obesity, fatty liver hyperlipidemia, atherosclerosis. Building upon this framework, afford description proteins pathways involved by focusing on PTM-based protein modifications, showcase pharmaceutical intervention preclinical studies clinical trials, future perspectives. Fundamental research defining mechanisms whereby regulate open new avenues therapeutic intervention.

Язык: Английский

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PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Март 30, 2023

Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these is often related adaptive changes in target oncoprotein which reduce binding affinity. The arsenal therapies, moreover, lacks coverage several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality deplete protein by hijacking cellular destruction machinery. offer advantages therapy including resiliency acquired mutations protein, enhanced selectivity, lower dosing requirements, and potential abrogate oncogenic transcription factors scaffolding proteins. Herein, we review development proteolysis targeting chimeras (PROTACs) selected targets reported biological activities. medicinal chemistry PROTAC design has been area active research, but recent advances field will usher an era rational degrader design.

Язык: Английский

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Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Июль 25, 2024

Abstract Ubiquitination, a pivotal posttranslational modification of proteins, plays fundamental role in regulating protein stability. The dysregulation ubiquitinating and deubiquitinating enzymes is common feature various cancers, underscoring the imperative to investigate ubiquitin ligases deubiquitinases (DUBs) for insights into oncogenic processes development therapeutic interventions. In this review, we discuss contributions ubiquitin–proteasome system (UPS) all hallmarks cancer progress drug discovery. We delve multiple functions UPS oncology, including its regulation cancer-associated pathways, metabolic reprogramming, engagement with tumor immune responses, function phenotypic plasticity polymorphic microbiomes, other essential cellular functions. Furthermore, provide comprehensive overview novel anticancer strategies that leverage UPS, application proteolysis targeting chimeras (PROTACs) molecular glues.

Язык: Английский

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Selenium chemistry for spatio-selective peptide and protein functionalization

Nature Reviews Chemistry, Год журнала: 2024, Номер 8(3), С. 211 - 229

Опубликована: Фев. 22, 2024

Язык: Английский

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Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin

Molecular Therapy — Nucleic Acids, Год журнала: 2022, Номер 30, С. 66 - 79

Опубликована: Сен. 19, 2022

PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack cell-type selectivity and are poorly soluble in water. To address this drawback, we developed novel PROTAC ZL216 using aptamer AS1411 targeting ligand of nucleolin to conjugate with small molecule E3 ligase VHL, which shows high aqueous solubility serum stability. Based on differential expression cell surface, could bind internalize into breast cancer cells, but not normal cells. Furthermore, revealed that promoted formation nucleolin-ZL216-VHL ternary complex cells potently induced vitro vivo. As result, inhibited proliferation migration These studies demonstrate addition peptides compounds, nuclei acid aptamers can also be used generate PROTACs, broadens toolbox constructing provides promising development tumor-selective PROTACs.

Язык: Английский

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Deubiquitylating Enzymes in Cancer and Immunity

Advanced Science, Год журнала: 2023, Номер 10(36)

Опубликована: Окт. 27, 2023

Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing post-translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type linkage or positions within chains. Moreover, several perform functions through specific protein-protein interactions in catalytically independent manner, which further expands versatility and complexity DUBs' functions. Dysregulation disrupts dynamic equilibrium causes various diseases, especially cancer immune disorders. This review summarizes Janus-faced roles including proteasomal degradation, DNA repair, apoptosis, tumor metastasis, as well immunity involving innate receptor signaling inflammatory autoimmune The prospects challenges clinical development DUB inhibitors are discussed. provides comprehensive understanding multi-faced immunity.

Язык: Английский

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Structure of the human UBR5 E3 ubiquitin ligase

Structure, Год журнала: 2023, Номер 31(5), С. 541 - 552.e4

Опубликована: Апрель 10, 2023

Язык: Английский

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