Bioorthogonal Aptamer‐ATTEC Conjugates for Degradation of Alpha‐Synuclein via Autophagy‐Lysosomal Pathway

Abstract Autophagosome‐tethering compound (ATTEC) technology has recently been emerging as a novel approach for degrading proteins of interest (POIs). However, it still faces great challenges in how to design target‐specific ATTEC molecules. Aptamers are single‐stranded DNA or RNA oligonucleotides that can recognize their target proteins with high specificity and affinity. Here, ATTEC is combined with aptamers for POIs degradation. As a proof of concept, pathological protein α‐synuclein (α‐syn) is chosen as the target and an efficient α‐syn degrader is generated. Aptamer as a targeting warhead of α‐syn is conjugated with LC3B‐binding compound 5,7‐dihydroxy‐4‐phenylcoumarin (DP) via bioorthogonal click reaction. It is demonstrated that the aptamer conjugated with DP is capable of clearing α‐syn through LC3 and autophagic degradation. These results indicate that aptamer‐based ATTECs are a versatile approach to degrade POIs by taking advantage of the well‐defined different aptamers for targeting diverse proteins, which provides a new way for the design of ATTECs to degradation of targeted proteins.