The FDA has approved an expanded indication for Risdiplam (Evrysdi; Genentech) to include the treatment of presymptomatic babies under 2 months old with spinal muscular atrophy (SMA), making it the first approved treatment administered at home for this patient group. Risdiplam is now approved to treat SMA in both children and adults of all ages. Risdiplam addresses the underlying cause of SMA: a reduced amount of survival motor neuron (SMN) protein. The protein is encoded by the SMN1 and SMN2 genes. SMA is caused by mutations in SMN1 that code for inactive forms of the protein. The activity of the SMN2 gene, which produces much smaller quantities of SMN, tends to determine the severity of disease. The compound is a pyridazine derivative that modifies the splicing of SMN2 messenger RNA to include exon 7, resulting in an increase in the concentration of the functional SMN protein in vivo. Nusinersen, the first drug approved to treat SMA, an anti-sense oligonucleotide targeting intronic splicing silencer N1 (ISS-N1), also alters mRNA splicing of SMN2, but using a different mechanism. Here you can see a theoretical model obtained by docking and molecular dynamics simulations showing how a Risdiplam analogue binds to a minimal RNA sequence. Previous studies demonstrated that Risdiplam and its analogues have two separate binding sites in exon 7 of the SMN2 pre-mRNA: (1) the 5’-splice site and (2) an upstream purine (GA)-rich binding site. Importantly, the sequence of this GA-rich binding site significantly enhanced the potency of a Risdiplam analogues, SMN-C2. The minimum required binding sequence for SMN-C2 was identified as GAAGGAAGG. SMN-C2 binds to both DNAs and RNAs that contain this 9-nucleotide sequence (Source: modelarchive ref. ma-fxj31)
#molecularart … #immolecular … #splicing … #Risdiplam … #theoretical … #model … #modulation … #spinal … #atrophy ... #moleculardynamics
Structure of the Risdiplam analogue in complex with RNA rendered with @proteinimaging and represented with @corelphotopaint
