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Recognition of single-stranded nucleic acids by small-molecule splicing modulators.

Zhichao Tang1, Sana Akhter2, Ankita Ramprasad1

  • 1Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.

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Summary

Risdiplam analogues bind to specific RNA sequences in spinal muscular atrophy (SMA) treatment. This study reveals a novel binding mode for SMN-C2, enhancing understanding of splicing modulator mechanisms.

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Area of Science:

  • Molecular Biology
  • Pharmacology
  • Biochemistry

Background:

  • Risdiplam is the first small-molecule splicing modulator approved for spinal muscular atrophy (SMA).
  • Previous research identified two binding sites for risdiplam analogues on SMN2 pre-mRNA: the 5'-splice site and an upstream GA-rich site.
  • The sequence of the GA-rich binding site is crucial for risdiplam analogue potency.

Purpose of the Study:

  • To determine the precise binding mechanism and sequence specificity of risdiplam analogue SMN-C2.
  • To elucidate the molecular basis of single-stranded purine-rich RNA recognition by splicing modulators.

Main Methods:

  • All-atom simulations using Gaussian accelerated molecular dynamics (GaMD).
  • Saturation transfer difference (STD) NMR.
  • Structure-affinity-relationship studies.

Main Results:

  • SMN-C2 binds to single-stranded GA-rich RNA in a sequence-specific manner.
  • The minimum binding sequence for SMN-C2 was identified as GAAGGAAGG.
  • A novel ligand-binding pocket formed by GAAG loop-like structures was discovered.
  • Simulation findings correlated well with experimental data.

Conclusions:

  • This study reveals an unprecedented binding mode for small-molecule splicing modulators.
  • Understanding the molecular basis of RNA recognition by risdiplam analogues is crucial for SMA treatment.
  • The findings provide insights into the mechanism of action for risdiplam and related compounds.