Directed evolution of genetically encoded LYTACs for cell-mediated delivery

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(13)

Опубликована: Март 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.

Язык: Английский

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Targeted Degradation of Cell‐Surface Proteins via Chaperone‐Mediated Autophagy by Using Peptide‐Conjugated Antibodies

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

Опубликована: Март 13, 2024

Cell-surface proteins are important drug targets but historically have posed big challenges for the complete elimination of their functions. Herein, we report antibody-peptide conjugates (Ab-CMAs) in which a peptide targeting chaperone-mediated autophagy (CMA) was conjugated with commercially available monoclonal antibodies specific cell-surface protein degradation by taking advantage lysosomal pathways. Unique features Ab-CMAs, including receptor- and E3 ligase-independent degradation, feasibility towards different (e.g., epidermal growth factor receptor (EGFR), programmed cell death ligand 1 (PD-L1), human 2 (HER2)) simple change antibody, successful tumor inhibition vivo, make them attractive degraders biomedical research therapeutic applications. As first example employing CMA to degrade from outside in, our findings may also shed new light on CMA, pathway typically cytosolic proteins.

Язык: Английский

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Subcellular targeting strategies for protein and peptide delivery

Advanced Drug Delivery Reviews, Год журнала: 2024, Номер 212, С. 115387 - 115387

Опубликована: Сен. 1, 2024

Язык: Английский

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Targeted degradation of membrane and extracellular proteins with LYTACs

Acta Pharmacologica Sinica, Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Язык: Английский

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A Bifunctional Lysosome‐Targeting Chimera Nanoplatform for Tumor‐Selective Protein Degradation and Enhanced Cancer Immunotherapy

Advanced Materials, Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Lysosome-targeting chimeras (LYTACs) have recently emerged as a promising therapeutic strategy for degrading extracellular and membrane-associated pathogenic proteins by hijacking lysosome-targeting receptors. However, the antitumor performance of LYTAC is limited its insufficient tumor accumulation nonspecific activation. Additionally, synergistic effects LYTACs other modalities are crucial. To address these issues, bifunctional nanoplatform (NLTC) developed tumor-selective protein degradation enhanced cancer immunotherapy. By rationally controlling surface composition, NLTC can effectively transport or membrane into lysosomes via cation-independent mannose 6-phosphate With removable modification, an obtained that efficiently accumulated in tissues avoided on-target off-tumor toxicity. Moreover, synthesis method generally applicable to various enzymes. Thus, catalase (CAT) encapsulated with synergistically degrade cell programmed death ligand-1 (PD-L1), relieve immunosuppressive microenvironment effective immunotherapy, significantly inhibit growth, recurrence, metastasis B16F10-bearing mice. This work presents not only perform tissue-selective but also integrate modalities, providing insights design advanced technologies clinical applications.

Язык: Английский

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Glycoscience in Advancing PD-1/PD-L1-Axis-Targeted Tumor Immunotherapy

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(3), С. 1238 - 1238

Опубликована: Янв. 31, 2025

Immune checkpoint blockade therapy, represented by anti-PD-1/PD-L1 monoclonal antibodies, has significantly changed the immunotherapy landscape. However, treatment is still limited unsatisfactory response rates, immune-related adverse effects, and drug resistance. Current studies have established that glycosylation, a common post-translational modification, crucial in promoting cancer progression immune invasion. Targeting aberrant glycosylation cancers presents precision medicine regimens for monitoring developing personalized medicine. Notably, checkpoints PD-1 PD-L1 are highly glycosylated, which affects PD-1/PD-L1 interaction binding of antibodies. Recent achievements glycoscience to enhance patient outcomes, referred as glycotherapy, underscored their high potency advancing therapies, i.e., glycoengineered antibodies with improved toward PD-1/PD-L1, pharmaceutic inhibitors core fucosylation sialylation, synergistic antibody-sialidase conjugate. This review briefly introduces axis highlights fundamental applied advances improve immunoblockade therapies.

Язык: Английский

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

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

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Systematic evolution of functional oligonucleotides for targeted protein degradation

Chem, Год журнала: 2025, Номер unknown, С. 102408 - 102408

Опубликована: Фев. 1, 2025

Язык: Английский

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Engineering IGF2 for Lysosome‐targeting chimeras development to target drug‐resistant membrane proteins in tumor therapy

Protein Science, Год журнала: 2025, Номер 34(3)

Опубликована: Фев. 19, 2025

Abstract Lysosome‐targeting chimeras (LYTACs) represent a promising approach for the targeted degradation of membrane proteins. Currently, two primary methods LYTAC development involve chemically modified antibodies and wild‐type insulin‐like growth factor 2 (IGF2) fusion proteins (iLYTACs). However, LYTACs necessitate intricate chemical modification processes, while IGF2 in iLYTAC technology binds to IGF1R, potentially triggering carcinogenesis. To tackle this challenge, we introduce specific IGF2R‐binding lysosomal targeting (sLYTACs), novel utilizing engineered mutant endogenous Diverging from iLYTACs, sLYTACs exhibit selective binding IGF2R with increased affinity, significantly bolstering anti‐proliferative impact on drug‐resistant tumor cells both vitro vivo. By effectively degrading third‐generation tyrosine kinase inhibitor‐resistant EGFR mutants, masking epitope HER2, concurrently compensatory receptors interacting these proteins, show great promise drug overcome bypass signaling combat resistance tumors.

Язык: Английский

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Insulin-like growth factor-1 (IGF-1) empowering tendon regenerative therapies

Frontiers in Bioengineering and Biotechnology, Год журнала: 2025, Номер 13

Опубликована: Март 27, 2025

Tendon injury is one of the most common musculoskeletal disorders that severely affect patients’ daily lives. Unfortunately, naturally healed tendons exhibit poor quality, as they have very limited regenerative ability. Recently, therapeutic strategies involving administration growth factors been advocated to enhance tendon healing. Growth are peptide-signaling molecules elicit biological functions such cell proliferation, migration, and differentiation by acting through a complex organization surface receptors activating intracellular signaling pathways. Insulin-like factor-1(IGF-1) represents factor has shown promising effects for enhancing healing in vitro animal models. However, it disappointing IGF-1 not play significant role promoting clinical trials, which could reflect our understanding molecular mechanisms involved Therefore, this review, we summarized roles Nevertheless, much work still needed optimize its effectiveness.

Язык: Английский

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