small molecule targeting α-synuclein mRNA

The protein α-synuclein is an important drug target for the treatment of Parkinson’s disease, but it is an intrinsically disordered protein lacking typical small molecule binding pockets. The mRNA encoding α-synuclein (SNCA), on the other hand, has regions of ordered structure in the 5’ untranslated region (UTR) near the start codon. Here, we present an integrated approach to identify small molecules that bind this structure and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5’UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that mechanistically inhibits ribosomes from assembling onto SNCA mRNA. We further converted it into a ribonuclease recruiting chimera (RIBOTAC) to degrade the SNCA mRNA in cells with improved potency. RNA-seq and proteomics studies demonstrated that Synucleozid-RIBOTAC (Syn-RIBOTAC) is selective in cells. Syn-RIBOTAC also improved ~50% of genes abnormally expressed in patient-derived iPSC-induced dopamine neurons. The RIBOTAC optimization strategy improved the bioactivity of lead compound by at least 5-fold. Broadly, one strategy to expand druggability of the proteome is to target the mRNAs that encode for “undruggable” proteins.

This is the supplemental dataset for our manuscript currently published at PNAS (doi: 10.1073/pnas.2306682120)