Targeted protein degradation (TPD) technologies can specifically identify and degrade target proteins by hijacking the inherent protein degradation pathways in cells.

Some of the extracellular and membrane-associated proteins are key agents in cancer, ageing-related diseases, autoimmune disorders, etc. Therefore, a general strategy to selectively degrade these proteins will offer new opportunities for drug discovery. 

Recently, a research team led by Profs. FANG Lijing, CHEN Liang, and LI Hongchang from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences has reported a novel integrin-facilitated lysosomal degradation (IFLD) strategy using bifunctional compounds as molecular degraders to degrade extracellular and cell membrane-associated proteins. 

This work was published in Journal of the American Chemical Society on Nov. 23.

The researchers prepared the molecular degrader through the conjugation of a target protein-binding ligand with an integrin-recognition ligand. "The molecular degrader was proved to be highly efficient to induce endocytosis and subsequent lysosomal degradation of extracellular or cell membrane-associated proteins through forming a ternary complex between the target protein and integrin on cell surface," said Prof. FANG.

Compared with antibody-, nanobody-, and aptamer-based technologies, bifunctional molecules possess several advantages as protein degraders such as small size, no immunogenicity, as well as controllable pharmacological and pharmacokinetic properties.

"The availability of small molecule inhibitors for many disease-related proteins also provides convenience for the design of IFLD molecular degraders," said Prof. CHEN.

"The IFLD strategy expands the toolbox for regulation of secreted and membrane-associated proteins, and thus it has great potential to be applied in chemical biology and drug discovery," said Prof. LI.

Integrin-facilitated lysosomal degradation (IFLD) strategy for extracellular or membrane-associated proteins using bifunctional compounds as molecular degraders. (Image by FANG Lijing)