IGF2 Peptide-Based LYTACs for Targeted Degradation of Extracellular and Transmembrane Proteins DOI Creative Commons
Michał Mikitiuk,

Jan Barczyński,

Przemysław Bielski

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 30, 2023

Abstract Lysosome Targeting Chimeras (LYTACs) have recently been developed to facilitate lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described date are based on glycopeptide conjugates, which difficult prepare produce a large scale. Here we report development pure protein LYTACs non-glycosylated IGF2 peptides, can be readily produced in virtually any facility capable monoclonal antibody production. These chimeras utilize IGF2R/CI-M6PR pathway for shuttling and, our illustrative example, target programmed death ligand 1 (PD-L1), eliciting physiological effects analogous immune checkpoint blockade. Results from vitro assays significantly exceed anti-PD-L1 antibodies alone.

Language: Английский

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
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
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
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
Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics DOI

Lisha Ou,

Mekedlawit Setegne,

Jeandele Elliot

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

The nascent field of targeted protein degradation (TPD) could revolutionize biomedicine due to the ability degrader molecules selectively modulate disease-relevant proteins. A key limitation broad application TPD is its dependence on small-molecule ligands target proteins interest. This leaves unstructured or those lacking defined cavities for binding out scope many technologies. use proteins, peptides, and nucleic acids (otherwise known as "biologics") protein-targeting moieties in degraders addresses this limitation. In following sections, we provide a comprehensive critical review studies that have used peptides mediate hence functional control otherwise challenging targets. We describe existing platforms protein/peptide-based ligand identification drug delivery systems might be exploited biologic-based degraders. Throughout Review, underscore successes, challenges, opportunities using protein-based chemical biology tools spur discoveries, elucidate mechanisms, act new therapeutic modality.

Language: Английский

Citations

0
An updated review on the role of small molecule in mediating protein degradation DOI

Zumei Wu,

Yulong Li, Jinyun Dong

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 287, P. 117370 - 117370

Published: Feb. 4, 2025

Language: Английский

Citations

0
A Plug‐and‐Play Ferritac Platform Degrading Membrane Proteins via Receptor Crosslinking DOI Open Access

Qunye He,

Lei Wang, Lulu Huang

et al.

Advanced Functional Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Membrane protein degradation techniques hijacking lysosome targeting receptors (LTRs) have provided new opportunities to develop anticancer therapeutics. However, due varied expression of these LTRs and potential influence on their native biological function resulting from excessive endocytosis, developing alternative membrane degraders is highly desirable. Here, Ferritac (ferritin‐based chimeras) developed, a plug‐and‐play platform that displayed multivalent antibodies via Spycatcher‐Spytag chemistry crosslink the ectodomains nearby for degradation. Based receptor crosslinking, obviates dependence specific LTRs. This study reveals nanoparticles efficiently degraded epidermal growth factor (EGFR) both in vitro vivo. In mechanistic studies, Ferritac‐Anti‐EGFR adopted clathrin‐based endocytosis mainly involved with pathways degradation, which are successfully expanded degrade PD‐L1 (programmed death‐ligand 1) HER2 (human 2) vitro. Moreover, efficient by Ferritac‐Anti‐PD‐L1 induce potent immune response vivo validated MC38 B16F10 tumor models. Further combined chemotherapeutics paclitaxel, saw satisfactory synergistic therapeutic effect. Overall, could be easily applied various targets directly attaching relevant promising candidate as novel versatile LTR‐independent degrader.

Language: Английский

Citations

0
Recent advances in degraders engaging lysosomal pathways and related nanomedicine DOI

Runxin Lu,

Xiaofeng Ni, Sha Diao

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 292, P. 117701 - 117701

Published: April 28, 2025

Language: Английский

Citations

0
Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs DOI Creative Commons
Md. Abdullah Al Mamun, Anush Bakunts, Alexander Chernorudskiy

et al.

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: May 1, 2025

Language: Английский

Citations

0