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Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism
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Tendencias emergentes en la caracterización de los diastereómeros de oligonucleótidos
Alexandre Goyon1, Daniel Ngoc Nguyen1, Kelly Zhang1
1Synthetic Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Journal of chromatography. A
|September 2, 2025
Resumen
La caracterización de los diastereómeros de oligonucleótidos terapéuticos es compleja. Los avances recientes en la espectrometría de masas de movilidad iónica y HILIC ofrecen nuevos enfoques analíticos, pero siguen existiendo desafíos para identificar configuraciones quirales y mejorar la separación.
Área de la Ciencia:
- Química analítica
- Ciencias Farmacéuticas
- Biotecnología
Sus antecedentes:
- Las modificaciones químicas mejoran la terapéutica de los oligonucleótidos pero complican el análisis.
- Los oligonucleótidos modificados por fosfato (PS) forman mezclas diastereoméricas complejas, que requieren métodos analíticos sólidos.
- Los organismos reguladores exigen una distribución diastereomérica precisa y una reproducibilidad entre lotes para los fármacos oligonucleótidos.
Objetivo del estudio:
- Revisar críticamente las tecnologías recientes (después de 2023) para el análisis de los diastereómeros de oligonucleótidos.
- Destacar los desafíos persistentes en la caracterización de los oligonucleótidos terapéuticos modificados por PS.
- Para cerrar la brecha analítica en la comprensión de la complejidad de los diastereómeros de oligonucleótidos.
Principales métodos:
- Revisión de la literatura reciente sobre las técnicas analíticas de los diastereómeros de oligonucleótidos.
- Se centrará en la espectrometría de masas de movilidad iónica (IM-MS) y la cromatografía líquida de interacción hidrófila (HILIC).
- Examen de los métodos para la identificación de las configuraciones quirales del enlace PS (Sp/Rp).
Principales resultados:
- Mejora limitada del número máximo de diastereómeros separables (32) a pesar de las nuevas técnicas.
- El IM-MS y el HILIC son prometedores, pero se enfrentan a desafíos en la caracterización integral de los diastereómeros.
- La investigación en curso tiene como objetivo mejorar la identificación de la estereoquímica del enlace PS.
Conclusiones:
- La caracterización analítica de los diastereómeros terapéuticos de oligonucleótidos sigue siendo un desafío significativo.
- Los avances en IM-MS y HILIC son cruciales, pero requieren un mayor desarrollo para la separación e identificación completa de los diastereómeros.
- Abordar estas lagunas analíticas es esencial para el uso seguro y eficaz de los oligonucleótidos terapéuticos.
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