Therapeutic phosphorodiamidate morpholino oligonucleotides: Physical properties, solution structures, and folding
Farkhad Maksudov1, Evgenii Kliuchnikov1, Daniel Pierson2
1Department of Chemistry, University of Massachusetts, Lowell, MA 01854, USA.
Molecular Therapy. Nucleic Acids
|March 13, 2023
Summary
Researchers revealed the solution structures of therapeutic phosphorodiamidate morpholino oligonucleotides (PMOs). These findings advance understanding of PMO structure-property relationships for designing novel RNA-mimic drugs.
Area of Science:
- Biochemistry and Biophysics
- Drug Design and Development
- Oligonucleotide Therapeutics
Background:
- Therapeutic RNA mimics like phosphorodiamidate morpholino oligonucleotides (PMOs) are crucial for treating genetic disorders such as Duchenne muscular dystrophy.
- Despite FDA approval, the lack of structural information for PMOs hinders a full understanding of their structure-function relationships.
- Charge-neutral and stable PMOs present unique challenges in structural elucidation.
Purpose of the Study:
- To resolve the solution structures of various length PMOs (22-mer, 25-mer, 30-mer).
- To investigate the conformational dynamics and thermodynamic stability of PMOs.
- To establish principles for understanding the structure-properties-function relationship of therapeutic PMOs.
Main Methods:
- Circular dichroism spectroscopy.
- Solution viscosity measurements.
- Molecular dynamics simulations and machine learning analyses.
Main Results:
- PMO structures are dictated by the interplay between nucleobases and phosphorodiamidate groups for solvent shielding.
- PMOs adopt non-canonical, partially helical, stable folded structures with small gyration radii and limited base pairing/stacking.
- Thermodynamic analysis revealed significant free energy, enthalpy, and entropy contributions to PMO folding.
- Viscosity measurements indicated extended and aggregating PMO systems, with high Huggins constants.
Conclusions:
- A conformational ensemble perspective is essential for understanding PMO solution structures.
- The thermodynamic stability of non-canonical PMO structures is a key characteristic.
- Concentration-dependent viscosity properties are critical for PMO behavior.
- These insights provide a paradigm for advancing the design of new RNA-mimic drugs.
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