RNA‐PROTACs: Degraders of RNA‐Binding Proteins

Abstract

Defects in the functions of RNA binding proteins (RBPs) are at the origin of many diseases; however, targeting RBPs with conventional drugs has proven difficult. PROTACs are a new class of drugs that mediate selective degradation of a target protein through a cell's ubiquitination machinery. PROTACs comprise a moiety that binds the selected protein, conjugated to a ligand of an E3 ligase. Herein, we introduce RNA‐PROTACs as a new concept in the targeting of RBPs. These chimeric structures employ small RNA mimics as targeting groups that dock the RNA‐binding site of the RBP, whereupon a conjugated E3‐recruiting peptide derived from the HIF‐1α protein directs the RBP for proteasomal degradation. We performed a proof‐of‐concept demonstration with the degradation of two RBPs—a stem cell factor LIN28 and a splicing factor RBFOX1—and showed their use in cancer cell lines. The RNA‐PROTAC approach opens the way to rapid, selective targeting of RBPs in a rational and general fashion.

Synergistic DNA‐ and Protein‐Based Recognition Promote an RNA‐Templated Bio‐orthogonal Reaction

“…This proximity‐induced reaction highlights the potential of structure‐based design in the development of such modular assemblies, particularly given the growing number of available protein/oligonucleotide complex structures [29,30] . Moreover, this expands both the complexity and functional spectrum of recent efforts towards chimeric molecules utilizing peptide and oligonucleotide features [31–36] . Taken together, our work serves as a proof‐of‐concept for the structure‐based design of peptide‐DNA conjugates possessing the ability to assemble into structurally‐defined complexes.…”

“…[ 29 , 30 ] Moreover, this expands both the complexity and functional spectrum of recent efforts towards chimeric molecules utilizing peptide and oligonucleotide features. [ 31 , 32 , 33 , 34 , 35 , 36 ] Taken together, our work serves as a proof‐of‐concept for the structure‐based design of peptide‐DNA conjugates possessing the ability to assemble into structurally‐defined complexes. Such systems can open the door to novel functional biomolecular assemblies.…”

Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation

“…This is highlighted by recent reports of RNA-PROTACs that use small molecule RNA mimics to bind and induce degradation of RNA binding proteins. 136 RNA itself can also now be degraded using newly developed heterobifunctional molecules, Ribonuclease targeting chimeras (RIBOTACs), which have timely implications for degrading viral SARS-CoV-2 RNA. 137,138 Additionally, DNA can now be used as a recruiting element to degrade ''undruggable'' transcription factors using our lab's newly developed TRAFTAC technology.…”

Applications of Bacterial Degrons and Degraders — Toward Targeted Protein Degradation in Bacteria

“…This includes light-activated PROTACs (Pfaff et al, 2019;Xue et al, 2019;Jin Y.H. et al, 2020;Liu J. et al, 2020;Manna and Wu, 2020;Reynders et al, 2020), RNA-PROTACs which target RNAbinding proteins (Ghidini et al, 2020), homo-PROTACs which are composed of two particles of the same E3 ligand (Maniaci et al, 2017;Steinebach et al, 2018), HaloPROTACs which are directed against the popular HaloTag (Buckley et al, 2015;Tovell et al, 2019;Simpson et al, 2020), and bioPROTACs composed of E3 ligase fused to known domains that interact with the target protein (Lim et al, 2020). Other techniques which exploit different degradation pathways are Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs) which have an activity similar to PROTACs but also induce the degradation of the associated ubiquitin ligases (Ohoka et al, 2017;Naito et al, 2019;Ishikawa et al, 2020), LYTACs which degrade extracellular proteins via lysosomal pathway (Banik et al, 2020) or autophagy-inducing AUTACs which can degrade fragmented mitochondria and proteins (Takahashi et al, 2019).…”