Modulating RNA Splicing by Small Molecules

11:00 a.m.

Zoom

Jingxin Wang (Assistant Professor, School of Pharmacy - Medicinal Chemistry, University of Kansas)

Risdiplam is the first approved small-molecule splicing modulator for the treatment of spinal muscular atrophy (SMA). We demonstrated that risdiplam analogs bind to a purine (GA)-rich sequence upstream to the splice site. The sequence of this GA-rich binding site significantly enhanced the potency of risdiplam analogs. A known risdiplam analog, SMN-C2, binds to single-stranded GA-rich RNA in a sequence-specific manner. The minimum required binding sequence for SMN-C2 was identified as GAAGGAAGG. To our knowledge, this is the first example of a consecutive primary RNA sequence consisting of 9 or more nucleotides being recognized by a single small molecule without the context of a G-quadruplex. We uncovered by molecular dynamic (MD) simulations, for the first time, a ligand-binding pocket formed by two sequential GAAG loop-like structures. This mechanistic understanding enabled us to design a new class of bispecific chimeric molecules to reduce the off-target effects of risdiplam analogs.