Aptamer-Based Targeted Protein Degradation

Abstract

The selective removal of misfolded, aggregated, or aberrantly overexpressed protein plays an essential role in maintaining protein-dominated biological processes. In parallel, the precise knockout of abnormal proteins is inseparable from the accurate identification of proteins within complex environments. Guided by these precepts, small molecules, or antibodies, are commonly used as protein recognition tools for developing targeted protein degradation (TPD) technology. Indeed, TPD has shown tremendous prospects in chronic diseases, rare diseases, cancer research, and other fields. Meanwhile, aptamers are short RNA or DNA oligonucleotides that can bind to target proteins with high specificity and strong affinity. Accordingly, aptamers are actively used in designing and constructing TPD technology. In this perspective, we provide a brief introduction to TPD technology in its current progress, and we summarize its application challenges. Recent advances in aptamer-based TPD technology are reviewed, together with corresponding challenges and outlooks.

Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy

“…Under ultrasound irradiation, the hematoporphyrin component produced ROS to induce endosomal/lysosomal rupture as well as ICD, and then released Cas9/sgRNA to knock down the IDO1 gene and thereby relieve immunosuppression . In addition to inhibitors and gene editing, targeted protein degradation (TPD), such as proteolysis targeting chimeras (PROTACs), lysosome targeting chimeras (LYTACs) and autophagy-targeting chimeras (AUTACs), is an emerging technology for degrading “undruggable” proteins . For example, PROTACs achieve protein degradation via covalent bonds between the target protein and E3 ubiquitin ligase, and the target protein is then ubiquitylated and degraded by the proteasome .…”

“…166 In addition to inhibitors and gene editing, targeted protein degradation (TPD), such as proteolysis targeting chimeras (PROTACs), lysosome targeting chimeras (LYTACs) and autophagy-targeting chimeras (AUTACs), is an emerging technology for degrading "undruggable" proteins. 167 For example, PROTACs achieve protein degradation via covalent bonds between the target protein and E3 ubiquitin ligase, and the target protein is then ubiquitylated and degraded by the proteasome. 168 Hence, TDP has great potential for application in metabolic reprogramming by targeting key enzymes in specific metabolic pathways.…”

Structural Optimization of Decoy Oligonucleotide-Based PROTAC That Degrades the Estrogen Receptor

“…3,4 Although small-molecule warheads are the most commonly used approach in PROTAC development, the use of oligonucleotides as warheads has recently been developed. 5 This innovation expands the scope of PROTAC technology by allowing the recruitment of proteins of interest (POI) for which optimal small-molecule ligands have not yet been identified. Oligonucleotide-based PROTACs are advantageous in that ligands can be easily designed and synthesized (as long as the binding sequence to the POI is known).…”

“…Chemical protein knockdown using proteolysis-targeting chimeras (PROTACs) is a powerful technology for degrading disease-related proteins by hijacking the endogenous ubiquitin–proteasome system (UPS). , PROTACs consist of three main components: a ligand for the target protein (warhead), a ligand for the ubiquitin E3 ligase, and a linker connecting the two ligands. PROTACs can degrade intracellular proteins such as protein kinases and transcription factors (TFs), including nuclear receptors and transcriptional regulators. , Although small-molecule warheads are the most commonly used approach in PROTAC development, the use of oligonucleotides as warheads has recently been developed . This innovation expands the scope of PROTAC technology by allowing the recruitment of proteins of interest (POI) for which optimal small-molecule ligands have not yet been identified.…”

Investigation of the Relationship between Aptamers’ Targeting Functions and Human Plasma Proteins

“…In vitro selection and modular solid-phase synthesis enable precisely controlled drug conjugation with aptamers and large-scale production without batch-to-batch variation. Collectively, such extraordinary merits contribute to the wide use of aptamers in different fields of biomedicine, such as biomonitoring, medical diagnosis, targeted therapy, etc. ,− By using the aptamers or their conjugations with drugs, cancer treatments based on the aptamers achieved excellent therapeutic effects in preclinical studies. , …”