Recently, a research group from the Hangzhou Institute of Medicine (HIM) of the Chinese Academy of Sciences (CAS) has proposed a click-constructed signal aptamer chimera (SApt) for efficient degradation of membrane proteins and even intracellular proteins via receptor-independent mechanism. This study was published in PNAS on May, 19, and led by Prof. Qu Fengli, in collaboration with Zhang Hui from the Hangzhou Institute for Advanced Study and University of Chinese Academy of Sciences (UCAS).

The emerging Targeted Protein Degradation (TPD) technology harnesses endogenous cellular mechanisms to proteins, thereby offering novel insights for drug development. Lysosome-Targeting Chimeras (LYTAC) represents a pioneering approach to efficiently eliminate pathogenic extracellular and membrane proteins through intracellular lysosomes. However, the heterogeneous expression of lysosome-targeted receptors (LTR) in different cell lines poses a great challenge to the clinical application of LYTACs.

In this work, the researchers have developed a SApt platform by conjugating a YXXØ sorting signal that derived from lysosome-associated membrane protein 2a (LAMP-2a) to the aptamer's terminus through efficient click chemical reaction.

Systematic research has revealed SApt facilitated the effective degradation of crucial membrane proteins, including PTK7, Met and NCL, in an aptamer binding- and YXXØ-dependent manner and that degradation involved clathrin/caveolin-mediated endocytosis and lysosome pathways, while not dependent in certain lysosome-targeted receptors (LTR).

In the chimeric SApt#Sgc8 system targeting the membrane protein PTK7, the scientists found that SApt#Sgc8 could induce alterations in cell internalization, leading to endosomal sorting and lysosomal trafficking. This process significantly degraded PTK7 on the cell membrane and triggered changes in downstream signaling pathways.

Both the in vitro and in vivo model demonstrate the continuous activity of SApt against tumors, and these suggest that the SApt platform holds great promise for clinical applications.

Contact:

Qu Fengli

Hangzhou Institute of Medicine

E-mail: qufengli@him.cas.cn