Current Status of Oligonucleotide-Based Protein Degraders

Abstract

Transcription factors (TFs) and RNA-binding proteins (RBPs) have long been considered undruggable, mainly because they lack ligand-binding sites and are equipped with flat and narrow protein surfaces. Protein-specific oligonucleotides have been harnessed to target these proteins with some satisfactory preclinical results. The emerging proteolysis-targeting chimera (PROTAC) technology is no exception, utilizing protein-specific oligonucleotides as warheads to target TFs and RBPs. In addition, proteolysis by proteases is another type of protein degradation. In this review article, we discuss the current status of oligonucleotide-based protein degraders that are dependent either on the ubiquitin–proteasome system or a protease, providing a reference for the future development of degraders.

Expanding the horizons of targeted protein degradation: A non-small molecule perspective

“…This category encompasses TFs, RNA-binding proteins (RBPs), and G-quadruplex (G4) binding proteins, demonstrating potential accessibility to nucleic acid sequences. This revelation opens avenues for the construction of targeted chimeras tailored to these proteins 55 , 56 . The seminal demonstration of the TPD strategy employing nucleic acid sequences as a warhead materialized in 2021 with the unveiling of transcription-factor-targeting chimeras (TRAFTACs) 57 .…”

“…Foremost, the design and development of nucleic acid warheads afford relative independence in optimizing chemical modifications and metabolic properties, in contrast to their small molecule and antibody counterparts. This expedites the preparatory phases and screening endeavors for potential nucleic acid warheads 55 , 56 . Additionally, the integration of aptamers into PROTAC construction, whether as an adjunct or as the warhead itself, bestows the resultant protein-degrading chimeras with commendable physicochemical attributes, coupled with tumor-specific targeting proficiency 16 , 64 .…”