Linker Length Optimization of Bispecific DNA Aptamer-Based HER2 Targeting Lysosome-Targeting Chimera (HER2-LYTAC)

Lysosome-targeting chimera (LYTAC) efficiently degrades specific membrane proteins. In a previous study, we synthesized and reported human epidermal growth factor receptor 2 (HER2)-LYTAC (that induces the degradation of HER2 protein using DNA aptamers that binds to insulin-like growth factor receptor 2 and HER2). In this study, we designed and synthesized linker-length-modified HER2-LYTAC derivatives with varying distances between the DNA aptamers and assessed their protein degradation-inducing activity. The results revealed that HER2 degradation varied significantly with the linker length. Notably, HL5L-HER2-LYTAC with a 5-bp longer linker than that of the original HER2-LYTAC-exhibited equivalent or enhanced activity and significantly inhibited the proliferation of HER2-positive cancer cells. This is the first study to assess the effect of linker length in designing LYTAC molecules using bispecific DNA aptamers and offers valuable insights into the molecular design of nucleic acid-based LYTACs.