There are limited examples of small molecules that target RNA and are approved drugs for the treatment of human disease. Ribavirin was approved in 2002 to treat Hepatitis C and viral hemorrhagic fever. As a nucleoside inhibitor, the guanosine analog prodrug is used to stop viral RNA synthesis and viral mRNA capping by incorporating into RNA and pairing to uracil or cytosine. Branaplam is currently in phase I/II clinical trial for the treatment of Spinal Muscular Atrophy (SMA). This molecule is from a class of pyridazine small molecules and enhances the inclusion of exon 7, resulting in a full-length and functional protein product.
Branaplam represents the first mechanistic study of splicing modulation using a sequence-selective small molecule. The drug stabilizes the transient double-stranded RNA (dsRNA) structure formed between the SMN2 pre-mRNA and U1 snRNP complex, a key component of the splicesome. Further, this compound acts by increasing the binding affinity of U1 snRNP to the 5’ splice site (5’ss) in a sequence-selective manner that is discrete from constitutive recognition. Ataluren is in clinical trials for the treatment of Duchenne Muscular Dystrophy (DMD). It is believed that Ataluren acts by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without affecting transcription, mRNA processing, mRNA stability, or protein stability to give nonsense suppression. This drug would be effective for ~10% of patients with DMD who have a single mutation in the DMD gene causing a stop codon to appear prematurely (nonsense mutation).