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.

Keywords: PROTAC; SNIPER; chimera; degrader therapeutics; nucleic acids; proteases; targeted protein degradation.

Figure 1

Schematic diagram of a PROTAC molecule and its degradation pathway. The degradation pathway is reliant on E1, E2, and E3 ligases and proteasome. The E3s are recruited to POI by PROTACs, thereby inducing ubiquitylation and proteasomal degradation.

Figure 2

Ubiquitination mechanisms of reported PROTAC-based technologies for targeting TFs or RBPs. These PROTAC molecules essentially consist of an E3 binder, a linking moiety, and a POI binder. The degradation of the POI is UPS-dependent.

Figure 3

Schematic representation of the design of an aptamer–PROTAC conjugate.

Figure 4

Schematic representation of the design of Apt-clean bispecific aptamer molecules. Essentially, Apt-clean bispecific aptamers consist of an aptamer for a POI (e.g., FGFR1) colored in blue, and another aptamer for a protease (e.g., thrombin) colored in green; generally, a linking moiety is not needed in between the aptamers. The degradation pathway is not UPS-dependent; instead, it relies on the protease activity of thrombin to initiate catalytic proteolysis.