Structure-Guided Modeling of Proteolysis-Targeting Chimera (PROTAC)-Aptamer Conjugates Targeting Nucleolin Protein in Glioblastoma

Glioblastoma (GBM) is an aggressive and fast-growing brain cancer with no known cure, and current research focuses on developing new strategies to slow its progression and improve patient outcomes. Nu- cleolin is an intracellular protein frequently overexpressed in cancer cells, where it plays key roles in cell cycle regulation, protein quality control, apoptosis, and antiviral immunity. Its upregulation contributes to oncogenesis, making it a critical therapeutic target in GBM. Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that induce targeted protein degradation by linking a target protein to an E3 ligase, leading to its ubiquitination and destruction by the proteasome. We hypothesize that an aptamer- based PROTAC can effectively bring nucleolin into proximity with an E3 ligase, thereby facilitating nu- cleolin’s proteasomal degradation. This research involves the computational modeling of the nucleolin protein, an E3 ligase, and a PROTAC-aptamer conjugate using AlphaFold. The results demonstrate that the designed aptamer binds strongly to a predicted site on nucleolin, and that the PROTAC architec-  ture enables proximity to the predicted binding site of an E3 ligase. This current research demonstrates the potential of aptamer-based PROTACs to selectively degrade oncogenic nucleolin proteins, offering a promising new approach to slow tumor growth and overcome therapeutic resistance. Future applications include the development of targeted treatments that improve patient outcomes.