Characterization and Sequence Mapping of Large RNA and mRNA Therapeutics Using Mass Spectrometry

Large RNA including mRNA (mRNA) has emerged as an important new class of therapeutics. Recently, this has been demonstrated by two highly efficacious vaccines based on mRNA sequences encoding for a modified version of the SARS-CoV-2 spike protein. There is currently significant demand for the develo...

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Published inAnalytical chemistry (Washington) Vol. 94; no. 20; pp. 7339 - 7349
Main Authors Vanhinsbergh, Christina J., Criscuolo, Angela, Sutton, Jennifer N., Murphy, Keeley, Williamson, Andrew J. K., Cook, Ken, Dickman, Mark J.
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 24.05.2022
Subjects
Analytical chemistry
Analytical methods
Annotations
Automation
Chemistry
Gene sequencing
Liquid chromatography
Mapping
Mass spectrometry
Mass spectroscopy
mRNA
Nucleotide sequence
Proteins
Ribonuclease T1
Sample preparation
Scientific imaging
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spectroscopy
Spike protein
Vaccines
Workflow
Online AccessGet full text

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Abstract Large RNA including mRNA (mRNA) has emerged as an important new class of therapeutics. Recently, this has been demonstrated by two highly efficacious vaccines based on mRNA sequences encoding for a modified version of the SARS-CoV-2 spike protein. There is currently significant demand for the development of new and improved analytical methods for the characterization of large RNA including mRNA therapeutics. In this study, we have developed an automated, high-throughput workflow for the rapid characterization and direct sequence mapping of large RNA and mRNA therapeutics. Partial RNase digestions using RNase T1 immobilized on magnetic particles were performed in conjunction with high-resolution liquid chromatography–mass spectrometry analysis. Sequence mapping was performed using automated oligoribo­nucleotide annotation and identifications based on MS/MS spectra. Using this approach, a >80% sequence of coverage of a range of large RNAs and mRNA therapeutics including the SARS-CoV-2 spike protein was obtained in a single analysis. The analytical workflow, including automated sample preparation, can be completed within 90 min. The ability to rapidly identify, characterize, and sequence map large mRNA therapeutics with high sequence coverage provides important information for identity testing, sequence validation, and impurity analysis.
AbstractList Large RNA including mRNA (mRNA) has emerged as an important new class of therapeutics. Recently, this has been demonstrated by two highly efficacious vaccines based on mRNA sequences encoding for a modified version of the SARS-CoV-2 spike protein. There is currently significant demand for the development of new and improved analytical methods for the characterization of large RNA including mRNA therapeutics. In this study, we have developed an automated, high-throughput workflow for the rapid characterization and direct sequence mapping of large RNA and mRNA therapeutics. Partial RNase digestions using RNase T1 immobilized on magnetic particles were performed in conjunction with high-resolution liquid chromatography–mass spectrometry analysis. Sequence mapping was performed using automated oligoribonucleotide annotation and identifications based on MS/MS spectra. Using this approach, a >80% sequence of coverage of a range of large RNAs and mRNA therapeutics including the SARS-CoV-2 spike protein was obtained in a single analysis. The analytical workflow, including automated sample preparation, can be completed within 90 min. The ability to rapidly identify, characterize, and sequence map large mRNA therapeutics with high sequence coverage provides important information for identity testing, sequence validation, and impurity analysis.
Large RNA including mRNA (mRNA) has emerged as an important new class of therapeutics. Recently, this has been demonstrated by two highly efficacious vaccines based on mRNA sequences encoding for a modified version of the SARS-CoV-2 spike protein. There is currently significant demand for the development of new and improved analytical methods for the characterization of large RNA including mRNA therapeutics. In this study, we have developed an automated, high-throughput workflow for the rapid characterization and direct sequence mapping of large RNA and mRNA therapeutics. Partial RNase digestions using RNase T1 immobilized on magnetic particles were performed in conjunction with high-resolution liquid chromatography–mass spectrometry analysis. Sequence mapping was performed using automated oligoribonucleotide annotation and identifications based on MS/MS spectra. Using this approach, a >80% sequence of coverage of a range of large RNAs and mRNA therapeutics including the SARS-CoV-2 spike protein was obtained in a single analysis. The analytical workflow, including automated sample preparation, can be completed within 90 min. The ability to rapidly identify, characterize, and sequence map large mRNA therapeutics with high sequence coverage provides important information for identity testing, sequence validation, and impurity analysis.
Large RNA including mRNA (mRNA) has emerged as an important new class of therapeutics. Recently, this has been demonstrated by two highly efficacious vaccines based on mRNA sequences encoding for a modified version of the SARS-CoV-2 spike protein. There is currently significant demand for the development of new and improved analytical methods for the characterization of large RNA including mRNA therapeutics. In this study, we have developed an automated, high-throughput workflow for the rapid characterization and direct sequence mapping of large RNA and mRNA therapeutics. Partial RNase digestions using RNase T1 immobilized on magnetic particles were performed in conjunction with high-resolution liquid chromatography–mass spectrometry analysis. Sequence mapping was performed using automated oligoribo­nucleotide annotation and identifications based on MS/MS spectra. Using this approach, a >80% sequence of coverage of a range of large RNAs and mRNA therapeutics including the SARS-CoV-2 spike protein was obtained in a single analysis. The analytical workflow, including automated sample preparation, can be completed within 90 min. The ability to rapidly identify, characterize, and sequence map large mRNA therapeutics with high sequence coverage provides important information for identity testing, sequence validation, and impurity analysis.
Author Dickman, Mark J.
Williamson, Andrew J. K.
Vanhinsbergh, Christina J.
Sutton, Jennifer N.
Murphy, Keeley
Criscuolo, Angela
Cook, Ken
AuthorAffiliation Department of Chemical & Biological Engineering
ThermoFisher Scientific GmbH
ThermoFisher Scientific
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Snippet Large RNA including mRNA (mRNA) has emerged as an important new class of therapeutics. Recently, this has been demonstrated by two highly efficacious vaccines...
Large RNA including mRNA (mRNA) has emerged as an important new class of therapeutics. Recently, this has been demonstrated by two highly efficacious vaccines...
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SubjectTerms Analytical chemistry
Analytical methods
Annotations
Automation
Chemistry
Gene sequencing
Liquid chromatography
Mapping
Mass spectrometry
Mass spectroscopy
mRNA
Nucleotide sequence
Proteins
Ribonuclease T1
Sample preparation
Scientific imaging
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spectroscopy
Spike protein
Vaccines
Workflow
Title Characterization and Sequence Mapping of Large RNA and mRNA Therapeutics Using Mass Spectrometry
URI http://dx.doi.org/10.1021/acs.analchem.2c00765
https://www.ncbi.nlm.nih.gov/pubmed/35549087
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