Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD‐L1 in Cancer Therapy DOI Creative Commons
Yazhen Wang, Zhou Yang,

Lianyi Yang

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 11(1)

Published: Nov. 7, 2023

Abstract Cancer immunotherapy using anti‐programmed death‐ligand 1 (PD‐L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, overall low patient response rate impede its further application. Mounting evidence revealed that PD‐L1 is not only present cell membrane but also cytoplasm, exosome, or even nucleus. Among these, the dynamic spatial heterogeneous expression of tumors mainly responsible for unsatisfactory efficacy antibodies. Hence, numerous studies focus on inhibiting degrading to improve immune response, while a comprehensive understanding molecular mechanisms underlying heterogeneity can fundamentally transform current status development. Herein, concept creatively introduced, encompassing structure biological functions kinds (including mPD‐L1, cPD‐L1, nPD‐L1, exoPD‐L1). Then an in‐depth analysis regulatory potential therapeutic targets provided, seeking offer solid basis future investigation. Moreover, agents summarized, especially small modulators development directed at these new targets, offering novel perspective therapeutics strategies.

Language: Английский

Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins DOI

Chenghong Zhu,

Weishan Wang, Yan Wang

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(13)

Published: Feb. 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.

Language: Английский

Citations

47
Current research status of anti-cancer peptides: Mechanism of action, production, and clinical applications DOI Open Access
Raj Kumar Chinnadurai,

Nazam Khan,

Gautam Kumar Meghwanshi

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 164, P. 114996 - 114996

Published: June 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.

Language: Английский

Citations

47
Targeted protein degradation directly engaging lysosomes or proteasomes DOI Creative Commons
Jiseong Kim, Insuk Byun, Do Young Kim

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(7), P. 3253 - 3272

Published: Jan. 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.

Language: Английский

Citations

28
Cell Membrane as A Promising Therapeutic Target: From Materials Design to Biomedical Applications DOI
Xiaofeng Wu, Jingjing Hu, Juyoung Yoon

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(18)

Published: Feb. 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.

Language: Английский

Citations

21
Expanding the horizons of targeted protein degradation: A non-small molecule perspective DOI Creative Commons
Xiaowei Huang, Fengbo Wu,

Jing Ye

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2402 - 2427

Published: Jan. 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

Language: Английский

Citations

19
A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy DOI Creative Commons
Youmei Xiao,

Zhuoying He,

Wanqiong Li

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 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

Language: Английский

Citations

6
Chemically engineered antibodies for autophagy-based receptor degradation DOI

Binghua Cheng,

Meiqing Li, Jiwei Zheng

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Language: Английский

Citations

2
Targeting intracellular cancer proteins with tumor‐microenvironment‐responsive bispecific nanobody‐PROTACs for enhanced therapeutic efficacy DOI Creative Commons
Changping Deng, Jiacheng Ma, Yuping Liu

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 19, 2025

Abstract Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, non‐specificity can lead systemic toxicity due protein degradation normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged tumor microenvironment enhance drug specificity. In this study, engineered BumPeD, novel bispecific nanobody‐targeted PROTACs‐like platform, by fusing two nanobodies with Furin protease cleavage site (RVRR) degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling direct of intracellular We utilized KN035 Nb4A target PD‐L1 (programmed death ligand 1) on cell surface Survivin, respectively. vitro experiments showed that BumPeD triggers Survivin via ubiquitin‐proteasome pathway, inducing apoptosis suppressing bladder proliferation migration. vivo further confirmed BumPeD's robust anti‐tumor efficacy, underscoring its potential as precise strategy therapy. Our platform provides systematic approach developing effective practical degraders, offering targeted theoretical basis experimental support development degradative drugs, well new directions

Language: Английский

Citations

2
PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies DOI Creative Commons

Nuwayo Ishimwe Sincere,

Krishnan Anand, Sumel Ashique

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(10), P. 4014 - 4014

Published: May 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.

Language: Английский

Citations

40
Nano Proteolysis Targeting Chimeras (PROTACs) with Anti‐Hook Effect for Tumor Therapy DOI

Ni‐Yuan Zhang,

Da‐Yong Hou, Xingjie Hu

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(37)

Published: July 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.

Language: Английский

Citations

40