Advances in the Specificity of Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy Based Structural Characterisation Methods for Synthetic Oligonucleotides |
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| Affiliation: | 1. Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK;2. Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, UK;3. New Modalities Parenteral Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK;4. Cellzome, Meyerhofstraße, Heidelberg, Germany;1. Biologics Drug Product Development, Novartis Pharma, Langkampfen, Austria;2. Biologics Analytical Development, Novartis Pharma, Langkampfen, Austria;1. Centre de recherche de l''Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval (CRIUCPQ-UL), Québec QC, Canada;2. Département de pharmacie de l''Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval (IUCPQ-UL), Québec QC, Canada;3. Centre de recherche du CHU de Québec Université Laval, Québec QC, Canada;4. Faculté de pharmacie, Université Laval, Québec QC, Canada;5. Faculté des sciences et de génie, Département de biochimie, de microbiologie et de bio-informatique, Université Laval, Québec QC, Canada;1. Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., Osaka, 561-0825, Japan;2. Sustainability Management Department, Shionogi & Co., Ltd., Osaka, 541-0045, Japan;3. Intellectual Property Department, Shionogi & Co., Ltd., Osaka, 541-0045, Japan;4. Analysis and Evaluation Laboratory, Shionogi & Co., Ltd., Osaka, 561-0825, Japan |
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| Abstract: | Identity testing is a critical part in the development of a therapeutic synthetic oligonucleotide. Tandem Mass Spectrometry (MS/MS) is commonly used for the analysis of oligonucleotides to obtain structural and sequence information, however there are challenges resulting from chemical modifications introduced to improve their pharmacokinetics and stability. For these structurally complex oligonucleotides, Nuclear Magnetic Resonance (NMR) Spectroscopy has found limited use for characterisation and identity testing, as only partial NMR resonance assignment for oligonucleotides is achieved without isotopic labelling methodologies. Regardless of the choice of method used for oligonucleotide analysis, the specificity is of critical importance. In this work, in-source dissociation mass spectrometry and proton (1H) and carbon (13C) NMR at high temperature were used to analyse danvatirsen, a 16 nucleotide phosphorothioate antisense oligonucleotide, and its closely related switch sequences. Both approaches have shown specificity to distinguish danvatirsen from these similar sequences. |
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