Conjugation with glucagon like peptide-1 enables targeted protein degradation

Liquan Zhu; Yiyu Zhou; Bei Zhang; Yin Luo; Chen Fang; Xiaoqiao Yan; Yefeng Cai; Linye Jiang; Jingyan Ge

doi:10.1016/j.bioorg.2023.106908

Conjugation with glucagon like peptide-1 enables targeted protein degradation

Bioorg Chem. 2023 Dec:141:106908. doi: 10.1016/j.bioorg.2023.106908. Epub 2023 Oct 7.

Authors

Liquan Zhu¹, Yiyu Zhou¹, Bei Zhang¹, Yin Luo¹, Chen Fang¹, Xiaoqiao Yan¹, Yefeng Cai², Linye Jiang¹, Jingyan Ge³

Affiliations

¹ Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China.
² Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
³ Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address: gejy@zjut.edu.cn.

PMID: 37827016
DOI: 10.1016/j.bioorg.2023.106908

Abstract

Lysosome-targeting chimeras (LYTACs) have emerged as a promising technique to extend the scope of targeted protein degradation to extracellular proteins, e.g., secreted proteins and membrane-anchored proteins. However, up to now, only a small number of lysosomal targeting receptors (LTRs), such as cation-independent mannose 6-phosphate receptor (CI-M6PR) and asialoglycoprotein receptor (ASGPR), were reported to build LYTACs for degradation of extracellular proteins. Therefore, it is important to explore more functionalized ligands for the relevant LTRs to expand the LYTAC framework. Herein, we demonstrate a new LTR ligand-glucagon like peptide 1 (GLP-1) based targeted degradation platform, termed GLP-1 receptor-targeting chimeras (GLP-1-LYTAC). GLP-1-LYTACs are formed by conjugating GLP-1 with targeted binder (such as antibody) through Click Chemistry, showing efficiently lysosomal degradation of both extracellular proteins (GFP and Neutravidin) as well as cell membrane proteins (EGFR and PD-L1). We believe that this novel GLP-1-LYTAC will open up a new dimension for targeted protein breakdown.

Keywords: EGFR; GLP-1; LYTAC; PD-L1; Protein degradation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Glucagon-Like Peptide 1*
Proteolysis

Substances

Glucagon-Like Peptide 1