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A universal LC-HRMS workflow integrating targeted and untargeted strategies for rapid and comprehensive metabolite profiling of oligonucleotide-based therapeutics

文献类型：期刊论文

作者Zhao, Yuqing1,3,4; Yang, Yue1; Zhu, Mingshe1,2; Tang, Chongzhuang1
刊名JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
出版日期2026-03-15
卷号270页码:9
关键词Oligonucleotide-based therapeutics Metabolites identification Background subtraction filter BioPharma finder Universal LC-HRMS workflow
ISSN号0731-7085
DOI10.1016/j.jpba.2025.117298
通讯作者Zhu, Mingshe(mingshe.zhu@xenofinder.com) ; Tang, Chongzhuang(chongzhuang.tang@xenofinder.com)
英文摘要Metabolite profiling and identification of oligonucleotide-based therapeutics (OBTs) is important in drug discovery and development. Conventional liquid chromatography-high resolution mass spectrometry (LC-HRMS) methods (using ProMass, BioPharma Finder) are effective for targeted analysis of predictable nuclease-derived metabolites but often miss unexpected non-nuclease-mediated ones. This study aimed to develop a universal analytical workflow for comprehensive metabolite profiling of multiple classes OBTs by integrating BioPharma Finder for targeted identification with a Background Subtraction Filter (BSF) for untargeted detection of unexpected biotransformation products. Inclisiran, a GalNAc-conjugated siRNA, was used as a model compound. Samples incubated with rat, monkey, and human liver S9 fractions were analyzed by the LC-HRMS workflow. As a result, a total of 25 (22 predicted +3 unpredicted) inclisiran metabolites were identified across the three species. BioPharma Finder enabled rapid and sensitive identification of 22 predicted metabolites, supported by automated fragment ion assignment. The BSF data processing revealed 22 metabolites not present in control samples, including SS-1GalNAc, SS-2GalNAc, and SS-3GalNAc, which were missed by BioPharma Finder and likely formed via beta-N-acetylglucosaminidase-mediated biotransformation. The structures of BSF-detected metabolites were confirmed by comparison with BioPharma Finder-identified metabolites or characterized through manual MS/MS interpretation. Product ion spectra of these metabolites showed weak or absent diagnostic ion (m/z 94.936), a characteristic fragment of phosphorothioate-containing oligonucleotides, suggesting that the product ion filtering of this ion exhibits limited utility in discovering inclisiran metabolites. Overall, the integrated LC-HRMS workflow shows strong potential as a universal platform for biotransformation studies of OBTs.
WOS关键词THOROUGH BACKGROUND SUBTRACTION ; RESOLUTION MASS-SPECTROMETRY ; LC/MS DATA APPLICATION ; RAT PLASMA ; IDENTIFICATION ; PHARMACOKINETICS ; ALGORITHM
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001638485200002
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/322405]  
专题中国科学院上海药物研究所
通讯作者Zhu, Mingshe; Tang, Chongzhuang
作者单位1.XenoFinder Co Ltd, Suzhou, Peoples R China
2.MassDefect Technol, Princeton, NJ USA
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
4.Tianjin Univ Tradit Chinese Med, Acad Tradit Chinese Med, Tianjin 301617, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Yuqing,Yang, Yue,Zhu, Mingshe,et al. A universal LC-HRMS workflow integrating targeted and untargeted strategies for rapid and comprehensive metabolite profiling of oligonucleotide-based therapeutics[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2026,270:9.
APA Zhao, Yuqing,Yang, Yue,Zhu, Mingshe,&Tang, Chongzhuang.(2026).A universal LC-HRMS workflow integrating targeted and untargeted strategies for rapid and comprehensive metabolite profiling of oligonucleotide-based therapeutics.JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,270,9.
MLA Zhao, Yuqing,et al."A universal LC-HRMS workflow integrating targeted and untargeted strategies for rapid and comprehensive metabolite profiling of oligonucleotide-based therapeutics".JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 270(2026):9.

入库方式： OAI收割

来源：上海药物研究所

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