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

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(18)

Published: Feb. 19, 2024

Abstract 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

From PROTAC to TPD: Advances and Opportunities in Targeted Protein Degradation DOI Creative Commons
Siqi Wang, Fuchu He, Chunyan Tian

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(1), P. 100 - 100

Published: Jan. 11, 2024

PROTAC is a rapidly developing engineering technology for targeted protein degradation using the ubiquitin–proteasome system, which has promising applications inflammatory diseases, neurodegenerative and malignant tumors. This paper gives brief overview of development design principles PROTAC, with special focus on PROTAC-based explorations in recent years aimed at achieving controlled improving bioavailability as well TPD technologies that use other pathways such autophagy lysosomes to achieve degradation.

Language: Английский

Citations

9
Directed evolution of genetically encoded LYTACs for cell-mediated delivery DOI Creative Commons
Jonathan Lee Yang, Sean A. Yamada‐Hunter, Louai Labanieh

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(13)

Published: March 21, 2024

Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here, we present our designs for fully encodable (GELYTAC), making tool compatible with integration into cells targeted delivery at diseased sites. To achieve this, replaced glycopeptide portion LYTACs protein insulin-like growth factor 2 (IGF2). After showing initial efficacy wild-type IGF2, increased potency GELYTAC using directed evolution. Subsequently, demonstrated engineered construct not only secretes from HEK293T but also human primary T-cells uptake various targets receiver cells. Immune secrete thus represent avenue spatially selective degradation.

Language: Английский

Citations

9
Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway DOI
Zhijie Wang, L. Yuan,

Xiaotong Liao

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6027 - 6043

Published: April 10, 2024

Targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has evolved into one of most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved treating a variety tumors, while development small-molecule PD-1/PD-L1 inhibitors lagged far behind, with only few entering clinical trials. In addition to and inhibitors, reducing expression levels PD-L1 attracted extensive research interest as another strategy target pathway. Herein, we analyze structures mechanisms molecules that reduce classify them degraders downregulators according whether they directly bind PD-L1. Moreover, discuss potential prospects developing PD-L1-targeting based on these molecules. It is hoped this perspective will provide profound insights discovery potent antitumor immunity drugs.

Language: Английский

Citations

9
Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation DOI

Jinyan Luo,

Quan Gao,

Kui Tan

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(26), P. 17728 - 17737

Published: June 20, 2024

Targeted protein degradation technology holds great potential in biomedicine, particularly treating tumors and other protein-related diseases. Research on intracellular using molecular glues PROTAC is leading, while research the of membrane proteins extracellular through lysosomal pathway still preclinical stage. The scarcity useful targets an immense limitation to technological advancement, making it essential explore novel, potentially effective approaches for targeted degradation. Here, we employed glucose transporter Glut1 as innovative lysosome-targeting receptor devised Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization acquired antibody-glycooligomer conjugates bioorthogonal reactions molecules, utilized management PD-L1 high-expressing triple-negative breast cancer. a exhibits advancement broader array medications future.

Language: Английский

Citations

9
Multivalent RGD Peptide-Mediated Nanochimera for Lysosomal Degradation of PDL1 Protein DOI

Yanfei Song,

Linjie Cui,

Zhilin Liu

et al.

Nano Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The development of immune checkpoint inhibitors, especially PDL1 antibodies, has revolutionized cancer therapy, but the posttherapy recycling proteins poses a significant challenge by inducing resistance and reducing treatment efficacy. To address this, we introduce an integrin-driven, lysosome-targeted nanochimera, composed poly(glutamic acid), RGD peptides, is designed to engage target protein, with αvβ3 integrin binding multivalent peptides direct complex through endocytosomal pathway lysosome, ensuring degradation blocking its recycling. Our in vitro vivo experiments demonstrate that these nanochimeras potently activate T-cell antitumor immunity downregulating expression within tumor cells tissues, significantly enhancing efficacy antibodies. A key discovery our study pivotal role facilitating protein degradation, providing valuable insights for more efficacious sophisticated immunotherapies.

Language: Английский

Citations

1
Cancer Specific CAIX‐Targeting Supramolecular Lysosome‐Targeting Chimeras (Supra‐LYTAC) for Targeted Protein Degradation DOI Creative Commons
Do‐Hyun Kim,

Gyeongseok Yang,

Chaelyeong Lim

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Recently, targeted protein degradation (TPD) strategies have emerged as a promising solution to tackle undruggable proteins. While most TPD target intracellular proteins, limited options exist for targeting extracellular or membrane Herein, cancer specific carbonic anhydrase IX (CAIX)-targeting supramolecular nanofibrous lysosome-targeting chimeras (Supra-LYTAC) is reported. Two self-assembling amphiphilic peptides are synthesized: one that interacts with the of interest (POI), and another mediates lysosomal endocytosis by cancer-specific enzyme. Notably, these two co-assemble into nanofibers capable cells in spatiotemporal manner. Through dynamic multivalent binding, ternary complex form (supramolecular chimeric nanostructure; CAIX-nanofiber-POI), which undergoes internalization lysosomes where POI degraded through catalytic activity. This study demonstrates potential approaches expand scope LYTAC technology, offering new opportunities designing future.

Language: Английский

Citations

1
Harnessing the Lysosomal Sorting Signals of the Cation-Independent Mannose-6-Phosphate Receptor for Targeted Degradation of Membrane Proteins DOI
Jinfeng Yu, Haonan Li, Fang Tong

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(34), P. 19107 - 19119

Published: Aug. 8, 2023

Membrane proteins are a crucial class of therapeutic targets that remain challenging to modulate using traditional occupancy-driven inhibition strategies or current proteolysis-targeting degradation approaches. Here, we report the inherent endolysosomal sorting machinery can be harnessed for targeted membrane proteins. A new technique, termed signal-mediated lysosome-targeting chimeras (SignalTACs), was developed by genetically fusing signaling motif from cation-independent mannose-6-phosphate receptor (CI-M6PR) protein binder. Antibody-based SignalTACs were constructed with CI-M6PR signal peptides fused C-terminus both heavy and light chains IgG. We demonstrated scope this platform technology degrading five pathogenesis-related proteins, including HER2, EGFR, PD-L1, CD20, CD71. Furthermore, two simplified constructs SignalTACs, nanobody-based peptide-based created shown promote lysosomal target Compared parent antibodies, exhibited significantly higher efficiency in inhibiting tumor cell growth vitro vivo. This work provides simple, general, robust strategy molecular precision may represent powerful broad research applications.

Language: Английский

Citations

21
Targeted degradation of extracellular secreted and membrane proteins DOI Creative Commons
Xuankun Chen,

Yaxian Zhou,

Yuan Zhao

et al.

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(11), P. 762 - 775

Published: Sept. 25, 2023

Language: Английский

Citations

18
SpyMask enables combinatorial assembly of bispecific binders DOI Creative Commons
C. Driscoll, Anthony H. Keeble, Mark Howarth

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 16, 2024

Bispecific antibodies are a successful and expanding therapeutic class. Standard approaches to generate bispecifics complicated by the need for disulfide reduction/oxidation or specialized formats. Here we present SpyMask, modular approach using SpyTag/SpyCatcher spontaneous amidation. Two SpyTag-fused antigen-binding modules can be precisely conjugated onto DoubleCatcher, tandem SpyCatcher where second is protease-activatable. We engineer panel of structurally-distinct DoubleCatchers, from which binders project in different directions. establish generalized methodology one-pot assembly purification 96-well plates. A recognizing HER2 epitopes were coupled revealing unexpected combinations with anti-proliferative pro-proliferative activity on HER2-addicted cancer cells. depended sensitively both binder orientation DoubleCatcher scaffold geometry. These findings support straightforward SpyMask provides scalable tool discover synergy bispecific activity, through modulating receptor organization

Language: Английский

Citations

7
Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins DOI Creative Commons

Yaxian Zhou,

Chunrong Li, Xuankun Chen

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 8, 2024

Targeted protein degradation has emerged as a novel therapeutic modality to treat human diseases by utilizing the cell's own disposal systems remove target. Significant clinical benefits have been observed for degrading many intracellular proteins. Recently, of extracellular proteins in lysosome developed. However, there limited successes selectively targets disease-relevant cells or tissues, which would greatly enhance development precision medicine. Additionally, most degraders are not readily available due their complexity. We report class easily accessible Folate Receptor TArgeting Chimeras (FRTACs) recruit folate receptor, primarily expressed on malignant cells, degrade soluble and membrane cancer-related vitro vivo. Our results indicate that FRTAC is general platform developing more precise effective chemical probes therapeutics study treatment cancers.

Language: Английский

Citations

6