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Exploiting Self-Association to Evaluate Enantiomeric Composition by Cyclic Ion Mobility-Mass Spectrometry.

ABSTRACT: The characterization of enantiomers is an important analytical challenge in the chemical and life sciences. Thorough evaluation of the purity of chiral molecules is particularly required in the pharmaceutical industry where safety concerns are paramount. Assessment of the enantiomeric composition is still challenging and time-consuming, meaning that alternative approaches are required. In this study, we exploit the formation of dimers as diastereomeric pairs of enantiomers to affect separation by high resolution cyclic ion mobility-mass spectrometry. Using the example of (R/S)-thalidomide, we show that even though this is not an enantiomer separation, we can determine which enantiomer is in excess and obtain quantitative information on the enantiomer composition without the need for a chiral modifier. Further examples of the approach are presented, including d/l-tryptophan and (R/S)-propanolol, and demonstrate the need for mobility resolving power in excess of 400 (CCS/ΔCCS).

SUBMITTER: Cooper-Shepherd DA

PROVIDER: S-EPMC9201813 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Exploiting Self-Association to Evaluate Enantiomeric Composition by Cyclic Ion Mobility-Mass Spectrometry.

Cooper-Shepherd Dale A DA Olivos Hernando J HJ Wu Zhaoxiang Z Palmer Martin E ME

Analytical chemistry 20220603 23

The characterization of enantiomers is an important analytical challenge in the chemical and life sciences. Thorough evaluation of the purity of chiral molecules is particularly required in the pharmaceutical industry where safety concerns are paramount. Assessment of the enantiomeric composition is still challenging and time-consuming, meaning that alternative approaches are required. In this study, we exploit the formation of dimers as diastereomeric pairs of enantiomers to affect separation b ...[more]

PMID: 35657797

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Project description:Therapeutic oligonucleotides such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA) are among the most remarkable modalities in modern medicine. ASOs and siRNA are composed of single- or double-stranded 15-25 mer synthesized oligonucleotides, which can be used to modulate gene expression. Liquid chromatography-mass spectrometry (LC/MS) is a necessary technique for the quality control of therapeutic oligonucleotides; it is used to evaluate the quantities of target oligonucleotides and their impurities. The widely applied oligonucleotide therapeutic quantitation method uses both ultraviolet (UV) absorbance and the MS signal intensity. Peaks separated from the main peak, which contains full-length product, are generally quantitated by UV. However, coeluting impurities, such as n - 1 shortmers, abasic oligonucleotides, and PS → PO (phosphorothiate to phosphodiester) oligonucleotides, are quantitated by MS. These coeluting impurities can also be comprised of various isomers with the same modification, thus increasing the difficulty in their separation and relative quantitation by LC/MS. It is possible that a specific isomer with a certain structural form induces toxicities. Therefore, characterization of each isomer separation is in high demand. In this study, we separated and characterized oligonucleotide isomers by employing a cyclic ion mobility mass spectrometry (cyclic IMS) system, which allows the separation of ions with the same m/z ratio based on their structural differences. Patisiran antisense and sense strands and their n - 1 and abasic isomers were used as sample sequences, and their ratio characterization was achieved by cyclic IMS. In addition, we evaluated the PS → PO conversion isomers of the antisense strand of givosiran, which originally contained four PS modification sites. The PS → PO isomers exhibited specific and distinguishable mobiligram patterns. We believe that cyclic IMS is a promising method for evaluating therapeutic oligonucleotide isomers.

Dataset Information

Exploiting Self-Association to Evaluate Enantiomeric Composition by Cyclic Ion Mobility-Mass Spectrometry.

Publications

Exploiting Self-Association to Evaluate Enantiomeric Composition by Cyclic Ion Mobility-Mass Spectrometry.

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