Development of Highly Efficient Lysosome-Targeting Peptide Ligands for the Internalization of Extracellular Proteins.
- 1School of Pharmacy, Lachman Institute of Pharmaceutical Development, University of Wisconsin-Madison, Madison, Wisconsin, USA.
- 2Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
- 3Chemical Biology, Novo Nordisk US R&D, Lexington, Massachusetts, USA.
Abstract
Lysosome-targeting chimeras (LYTACs) induce the internalization of extracellular and membrane-associated proteins by routing them to lysosomes via endogenous receptors, such as the insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor. While current IGF2R ligands are effective, expanding the LYTAC toolkit with structurally simple and synthetically accessible ligands remains a practical necessity. Here, we first validated that previously reported dimeric and monomeric peptides induce robust internalization, establishing them as effective IGF2R-targeting LYTAC ligands. To further optimize the peptide architecture, we performed systematic mutational scanning on its monomeric sequence to simplify the peptide architecture. We identified the L4 variant, which features a single leucine substitution at the fourth position. This optimized monomer induces greater internalization efficiency than the previously reported wild-type monomeric peptide ligand. To demonstrate its utility, we conjugated the L4 recruiter to a specific PCSK9 binder. The resulting bifunctional molecule successfully induced the dose- and time-dependent internalization of PCSK9. Collectively, these findings establish several peptide variants as practical and highly effective building blocks for the development of extracellular protein internalization platforms.
Related
- A lipoprotein-biomimetic nanoplatform for oncogenic KRAS mutation-specific lysosome-targeting protein degradation.
- Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering
- Targeting the Cav1.2-KCa1.1 axis prevents rabies virus internalization and protects against lethal infection
- Efficient base editing and development in human embryos without chromosomal alterations
- Sporulation modulates viscoelastic development through extracellular matrix restructuring in Bacillus subtilis biofilms
BibTeX
@article{zhao2026development,
title = {{Development of Highly Efficient Lysosome-Targeting Peptide Ligands for the Internalization of Extracellular Proteins.}},
author = {Yuan Zhao and Yaxian Liao and Xuankun Chen and Deqin Cai and Regina Stasser de Gonzalez and Hua Tang and Florence M Brunel and Nick Cox and Joseph Stock and Guangsen Fu and Alexander N Zaykov and Weiping Tang},
journal = {Chembiochem : a European journal of chemical biology},
year = {2026},
month = oct,
doi = {10.1002/cbic.70587},
url = {https://europepmc.org/article/MED/42952087},
note = {CC BY},
}
RIS
TY - JOUR
TI - Development of Highly Efficient Lysosome-Targeting Peptide Ligands for the Internalization of Extracellular Proteins.
AU - Yuan Zhao
AU - Yaxian Liao
AU - Xuankun Chen
AU - Deqin Cai
AU - Regina Stasser de Gonzalez
AU - Hua Tang
AU - Florence M Brunel
AU - Nick Cox
AU - Joseph Stock
AU - Guangsen Fu
AU - Alexander N Zaykov
AU - Weiping Tang
PY - 2026
DA - 2026/10/28
JO - Chembiochem : a European journal of chemical biology
DO - 10.1002/cbic.70587
UR - https://europepmc.org/article/MED/42952087
AB - Lysosome-targeting chimeras (LYTACs) induce the internalization of extracellular and membrane-associated proteins by routing them to lysosomes via endogenous receptors, such as the insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor. While current IGF2R ligands are effective, expanding the LYTAC toolkit with structurally simple and synthetically accessible ligands remains a practical necessity. Here, we first validated that previously reported dimeric and monomeric peptides induce robust internalization, establishing them as effective IGF2R-targeting LYTAC ligands. To further optimize the peptide architecture, we performed systematic mutational scanning on its monomeric sequence to simplify the peptide architecture. We identified the L4 variant, which features a single leucine substitution at the fourth position. This optimized monomer induces greater internalization efficiency than the previously reported wild-type monomeric peptide ligand. To demonstrate its utility, we conjugated the L4 recruiter to a specific PCSK9 binder. The resulting bifunctional molecule successfully induced the dose- and time-dependent internalization of PCSK9. Collectively, these findings establish several peptide variants as practical and highly effective building blocks for the development of extracellular protein internalization platforms.
SN - 1439-4227
SN - 1439-7633
ER -