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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PROTACs: past, present and future

Chemical Society Reviews, Год журнала: 2022, Номер 51(12), С. 5214 - 5236

Опубликована: Янв. 1, 2022

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein interest (POI) and another can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI ligase results in ubiquitination subsequent degradation by ubiquitin-proteasome system (UPS). event-driven mechanism action (MOA) PROTACs offers several advantages compared traditional occupancy-driven small molecule inhibitors, such as catalytic nature, reduced dosing frequency, more potent longer-lasting effect, added layer selectivity reduce potential toxicity, efficacy face drug-resistance mechanisms, targeting nonenzymatic functions, expanded target space. Here, we highlight important milestones briefly discuss lessons learned about targeted (TPD) recent years conjecture on efforts still needed expand toolbox for PROTAC discovery ultimately provide promising therapeutics.

Язык: Английский

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Proximity-Based Modalities for Biology and Medicine

ACS Central Science, Год журнала: 2023, Номер 9(7), С. 1269 - 1284

Опубликована: Июль 14, 2023

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of processes high selectivity has the potential to substantially expand target space. A plethora proximity-based modalities proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines mechanisms molecules based on induced proximity, including protein degraders, blockers, stabilizers, inducers post-translational modifications, agents cell therapy, discusses challenges that field must address mature unlock translation in biology medicine.

Язык: Английский

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Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(48), С. 21831 - 21836

Опубликована: Ноя. 23, 2022

As effective ways to regulate protein levels, targeted degradation technologies have attracted great attention in recent years. Here, we established a novel integrin-facilitated lysosomal (IFLD) strategy degrade extracellular and cell membrane proteins using bifunctional compounds as molecular degraders. By conjugation of target protein-binding ligand with an integrin-recognition ligand, the resulting degrader proved be highly efficient induce internalization subsequent or integrin- lysosome-dependent manner. demonstrated development BMS-L1-RGD, which is programmed death-ligand 1 (PD-L1) validated both vitro vivo, IFLD expands toolbox for regulation secreted membrane-associated thus has potential applied chemical biology drug discovery.

Язык: Английский

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The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

Chemical Reviews, Год журнала: 2023, Номер 123(12), С. 7782 - 7853

Опубликована: Май 15, 2023

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, basic research. A plethora chemical genetic approaches been devised to make accessible more "undruggable" targets equipped with new functions illustrating or regulating biological processes precisely. In this Review, addition introducing how naked various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide antibody-enzyme etc.) work therapeutic applications, special attention has paid chemistry tools helped optimize the outcome (i.e., enhanced efficacy reduced side effects) facilitate multifunctionalization antibodies, focus on emerging fields such targeted protein degradation, real-time live-cell imaging, catalytic labeling decaging spatiotemporal control well engagement inside cells. With advances modern biotechnology, well-designed derivatives via size miniaturization together efficient delivery systems emerged, which gradually improved our understanding important paved way pursue novel for potential treatments diseases.

Язык: Английский

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Targeted Degradation of PD‐L1 and Activation of the STING Pathway by Carbon‐Dot‐Based PROTACs for Cancer Immunotherapy

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(11)

Опубликована: Янв. 17, 2023

Abstract Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease‐associated proteins. Here, we report carbon‐dot (CD)‐based PROTACs (CDTACs) that membrane proteins via the ubiquitin‐proteasome system. CDTACs can bind programmed cell death ligand 1 (PD‐L1), recruit cereblon (CRBN) induce PD‐L1 ubiquitination, and them with proteasomes. Fasting‐mimicking diet (FMD) also used enhance cellular uptake proteasome activity. More than 99 % or 90 of in CT26 B16‐F10 tumor cells be degraded by CDTACs, respectively. Furthermore, activate stimulator interferon genes (STING) pathway trigger immune responses. Thus, FMD treatment effectively inhibit growth tumors. Compared small‐molecule‐based PROTACs, offer several advantages, such as efficient protein degradation, targeted accumulation, system activation, vivo detection.

Язык: Английский

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Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

Theranostics, Год журнала: 2023, Номер 13(5), С. 1520 - 1544

Опубликована: Янв. 1, 2023

Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on forms of various regulating mechanisms to enhance therapeutic effect, including blockade interaction between PD-1, downregulation expression degradation mature PD-L1. Thereinto, describe variety materials been designed target PD-L1, antibodies, nanoparticle, peptide, aptamer, RNA, small molecule. Additionally, list drugs regulation capacity used in clinical ongoing studies explore other alternatives besides anti-PD-L1 monoclonal antibodies. Moreover, discuss associated opportunities cancer combination therapy modalities such as chemotherapy, radiotherapy, photodynamic (PDT) photothermal (PTT), these conventional or emerging capable increasing cells by altering microenvironment (TME), would display synergistic effect. At last, give brief summary outlook regarding research status future prospect immunotherapy.

Язык: Английский

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Recent advances in chemical protein synthesis: method developments and biological applications

Science China Chemistry, Год журнала: 2024, Номер 67(4), С. 1060 - 1096

Опубликована: Март 12, 2024

Язык: Английский

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Aptamer-Based Targeted Protein Degradation

ACS Nano, Год журнала: 2023, Номер 17(7), С. 6150 - 6164

Опубликована: Март 21, 2023

The selective removal of misfolded, aggregated, or aberrantly overexpressed protein plays an essential role in maintaining protein-dominated biological processes. In parallel, the precise knockout abnormal proteins is inseparable from accurate identification within complex environments. Guided by these precepts, small molecules, antibodies, are commonly used as recognition tools for developing targeted degradation (TPD) technology. Indeed, TPD has shown tremendous prospects chronic diseases, rare cancer research, and other fields. Meanwhile, aptamers short RNA DNA oligonucleotides that can bind to target with high specificity strong affinity. Accordingly, actively designing constructing this perspective, we provide a brief introduction technology its current progress, summarize application challenges. Recent advances aptamer-based reviewed, together corresponding challenges outlooks.

Язык: Английский

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In Vivo Applications of Bioorthogonal Reactions: Chemistry and Targeting Mechanisms

Chemistry - A European Journal, Год журнала: 2023, Номер 29(20)

Опубликована: Янв. 19, 2023

Bioorthogonal chemistry involves selective biocompatible reactions between functional groups that are not normally present in biology. It has been used to probe biomolecules living systems, and advanced biomedical strategies such as diagnostics therapeutics. In this review, the challenges opportunities encountered when translating vitro bioorthogonal approaches vivo settings presented, with a focus on methods deliver reaction components. These include metabolic bioengineering, active targeting, passive simultaneously strategies. The suitability of ligation bond cleavage for applications is critically appraised, practical considerations optimum scheduling regimen pretargeting discussed. Finally, we our own perspectives area identify what, view, key must be overcome maximise impact these approaches.

Язык: Английский

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