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.
Highlights
RNA binding proteins (RBPs) constitute a large fraction of a cells proteome.[1]
Chemie ethyl (MOE) ribonucleotides and conjugated it to a E3recruiting peptide derived from the HIF-1a protein. This RNA-PROTAC binds selectively to Lin28 in vitro, and suppressed levels of Lin28A in two cancer cell lines in ubiquitin-dependent fashion. These findings pave the way to a new class of rationally designed inhibitors for RBPs, a protein family that until now has been difficult to address with conventional drugs
A short oligoribonucleotide corresponding to the consensus RNA consensus binding element (RBE) was a conceptually natural choice for the targeting element of an RNA PROTAC
Summary
RNA binding proteins (RBPs) constitute a large fraction of a cells proteome.[1]. Over 1500 RBPs are known and their genes are evolutionally conserved and transcribed into splicing variants with unique functions. The targeting ligand of a conventional PROTAC is a druglike small molecule that binds selectively to the POI. Angewandte Chemie International Edition published by Wiley-VCH GmbH Chemie ethyl (MOE) ribonucleotides and conjugated it to a E3recruiting peptide derived from the HIF-1a protein This RNA-PROTAC binds selectively to Lin in vitro, and suppressed levels of Lin28A in two cancer cell lines in ubiquitin-dependent fashion. Taken together, these findings pave the way to a new class of rationally designed inhibitors for RBPs, a protein family that until now has been difficult to address with conventional drugs
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