Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(13)

Опубликована: Фев. 3, 2023

Abstract Bispecific chimeras bridging cell membrane proteins with lysosome‐trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease‐relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses dendritic to engage surface scavenger (SRs) as LTR. Using bioorthogonal strain‐promoted alkyne‐azide cycloaddition conjugate the protein binder, resulting DENTAC is able traffic target into lysosome for elimination. We demonstrated utility by degrading oncogenic nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti‐cancer application NCL‐targeting was validated in mouse xenograft model lung cancer. This work thus presents new avenue rapid development potent degraders against proteins, also broad research prospects.

Язык: Английский

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Current research status of anti-cancer peptides: Mechanism of action, production, and clinical applications

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 164, С. 114996 - 114996

Опубликована: Июнь 11, 2023

The escalating rate of cancer cases, together with treatment deficiencies and long-term side effects currently used drugs, has made this disease a global burden the 21st century. number breast lung patients sharply increased worldwide in last few years. Presently, surgical treatment, radiotherapy, chemotherapy, immunotherapy strategies are to cure cancer, which cause severe effects, toxicities, drug resistance. In recent years, anti-cancer peptides have become an eminent therapeutic strategy for due their high specificity fewer toxicity. This review presents updated overview different peptides, mechanisms action current production employed manufacture. addition, approved under clinical trials applications been discussed. provides information on that hold great promise near future.

Язык: Английский

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Targeted protein degradation directly engaging lysosomes or proteasomes

Chemical Society Reviews, Год журнала: 2024, Номер 53(7), С. 3253 - 3272

Опубликована: Янв. 1, 2024

This review delineates emerging technologies for targeted protein degradation that directly involve lysosomes or proteasomes. It explores their unique features, advantages, and limitations, offering perspectives on future therapeutic applications.

Язык: Английский

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Cell Membrane as A Promising Therapeutic Target: From Materials Design to Biomedical Applications

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(18)

Опубликована: Фев. 19, 2024

The cell membrane is a crucial component of cells, protecting their integrity and stability while facilitating signal transduction information exchange. Therefore, disrupting its structure or impairing functions can potentially cause irreversible damage. Presently, the tumor recognized as promising therapeutic target for various treatment methods. Given extensive research focused on membranes, it both necessary timely to discuss these developments, from materials design specific biomedical applications. This review covers treatments based functional targeting membrane, ranging well-known membrane-anchoring photodynamic therapy recent lysosome-targeting chimaeras protein degradation. diverse mechanisms are introduced in following sections: phototherapy, self-assembly situ biosynthesis degradation proteins by chimeras. In each section, we outline conceptual general derived numerous studies, emphasizing representative examples understand advancements draw inspiration. Finally, some challenges future directions membrane-targeted our perspective. aims engage multidisciplinary readers encourage researchers related fields advance fundamental theories practical applications membrane-targeting agents.

Язык: Английский

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Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(6), С. 2402 - 2427

Опубликована: Янв. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Язык: Английский

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A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 6, 2025

The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, synthesis LYTACs, antibody-small molecule conjugates, is challenging. ability antibody-based LYTACs to penetrate solid tumor limited as well, especially cross blood-brain barrier (BBB). Here, we propose covalent chimeric peptide-based targeted platform (Pep-TACs) by introducing long flexible aryl sulfonyl fluoride group, which allows proximity-enabled cross-linking upon binding with protein interest. Pep-TACs facilitates target proteins through mechanism recycling transferrin receptor (TFRC)-mediated lysosomal endocytosis. Biological experiments demonstrate that can significantly degrade expression PD-L1 on cells, dendritic cells and macrophages, under acidic conditions, markedly enhance function T phagocytosis macrophages. Furthermore, both in anti-PD-1-responsive -resistant models, exert significant anti-tumor immune response. It noteworthy BBB prolong survival mice situ brain tumor. As proof-of-concept, this study introduces modular TFRC-based peptide protein, immunotherapy tumors. LYTAC strategies often face challenges penetration synthesis. authors introduce Pep-TACs, effectively degrades PD-L1. This approach suppresses growth, particularly

Язык: Английский

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PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

Molecules, Год журнала: 2023, Номер 28(10), С. 4014 - 4014

Опубликована: Май 10, 2023

A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted breakdown using PROTACs technology. Few medications now in use are tiny, component-based and utilize occupancy-driven pharmacology (MOA), which inhibits function short period time temporarily alter it. By utilizing an event-driven MOA, proteolysis-targeting chimeras (PROTACs) technology introduces revolutionary tactic. Small-molecule-based heterobifunctional hijack ubiquitin–proteasome system trigger degradation target protein. The main challenge PROTAC’s development facing find potent, tissue- cell-specific PROTAC compounds with favorable drug-likeness standard safety measures. ways increase efficacy selectivity focus this review. In review, we have highlighted most important discoveries related proteins PROTACs, new approaches boost proteolysis’ effectiveness development, promising future directions medicine.

Язык: Английский

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Nano Proteolysis Targeting Chimeras (PROTACs) with Anti‐Hook Effect for Tumor Therapy

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(37)

Опубликована: Июль 24, 2023

Abstract Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post‐translational protein degradation capabilities. However, off‐target induced unintended tissue effects and intrinsic “hook effect” hinder PROTAC biotechnology to be maturely developed. Herein, intracellular fabricated nano proteolysis chimeras (Nano‐PROTACs) a center‐spoke network for achieving efficient dose‐dependent in tumor reported. The precursors are triggered by higher GSH concentrations inside cells, which subsequently situ self‐assemble into Nano‐PROTACs through intermolecular hydrogen bond interactions. fibrous can form effective polynary complexes E3 ligases multi‐binding sites, “anti‐hook effect”. generality efficacy of validated degrading variable interest (POI) such as epidermal growth factor receptor (EGFR) androgen (AR) wide‐range manner 95 % rate long‐lasting potency up 72 h vitro. Significantly, achieve vivo 79 inhibition A549 LNCap xenograft mice models, respectively. Taking advantages self‐assembly strategy, the provide generalizable platform promote precise clinical translational application PROTAC.

Язык: Английский

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Covalent LYTAC Enabled by DNA Aptamers for Immune Checkpoint Degradation Therapy

Journal of the American Chemical Society, Год журнала: 2023, Номер unknown

Опубликована: Ноя. 1, 2023

Immune checkpoint blockade (ICB) therapy, while achieving tremendous clinical successes, still suffers from a low objective response rate in cancer treatment. As proof-of-concept study, we propose new immune degradation (ICD) therapy relying on lysosome-targeting chimera (LYTAC) to deplete programmed death ligand-1 (PD-L1) the tumor cell surface. Our designed chimeric aptamer one side targets lysosome-trafficking receptor, and other allows biorthogonal covalent-conjugation-reinforced specific binding of PD-L1. This covalent LYTAC is able hijack PD-L1 for lysosomal with greatly improved efficiency over its noncovalent counterpart complex vivo environment. Beyond abolishing PD-1/PD-L1 axis associated resistance, demonstrate first time that LYTAC-triggered could directly cause immunogenic apoptosis cells elicit tumor-specific responses, offering unparalleled advantages ICB antibody therapy. Remarkably, ICD achieves comparable or higher antitumor efficacy causing significantly less inflammatory injury compared antibody-based Moreover, can serve as general platform specifically degrading membrane-associated proteins, making it promising tool future applications. work presents novel molecular effective environments, valuable insights pushing DNA-based drugs toward

Язык: Английский

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PROTACs: Novel tools for improving immunotherapy in cancer

Cancer Letters, Год журнала: 2023, Номер 560, С. 216128 - 216128

Опубликована: Март 16, 2023

Язык: Английский

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