Studying the selectivity of a small molecule Synucleozid on transcriptome

One strategy to drugging undruggable proteins is to directly target the mRNA that encodes them, thereby inhibit translation and reducing protein levels. Inforna, a sequence-based design approach to target RNA, enables the design of a small molecule Synucleozid that binds SNCA mRNA which encodes alpha-synuclein. Herein, we investigate the selectivity of Synucleozid on the whole transcriptome. Based on mechanistic studies, Synucleozid targets IRE locates in 5' UTR of SNCA mRNA and reduces alpha-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes. Different from alpha-synuclein siRNA, Synucleozid binds mRNA and affect its function without regulating mRNA expression. Examination of small molecule-treated (Synucleozid) vs vehicle-treated (DMSO Vehicle) and alpha-synuclein siRNA-treated vs Scramble siRNA-treated SH-SY5Y cells in biological triplicates.