A direct peptide reactivity assay using a high-throughput mass spectrometry screening platform for detection of skin sensitizers

被引:11
|
作者
Wei, Zhengxi [1 ]
Fang, Yuhong [1 ]
Gosztyla, Maya L. [1 ]
Li, Andrew J. [1 ]
Huang, Wenwei [1 ]
LeClair, Christopher A. [1 ]
Simeonov, Anton [1 ]
Tao, Dingyin [1 ]
Xia, Menghang [1 ]
机构
[1] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA
基金
美国国家卫生研究院;
关键词
Direct peptide reaction assay (DPRA); RapidFire-MS/MS; High throughput mass spectrometry; LEAD DISCOVERY; KINASE INHIBITORS; CHEMICALS; COMBINATION; PREDICTION; CONTACT; HAPTENS; POTENCY;
D O I
10.1016/j.toxlet.2020.12.002
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Chemical-peptide conjugation is the molecular initiating event in skin sensitization. The OECD test guideline uses a high-performance liquid chromatography/ultraviolet (HPLC/UV) detection method to quantify chemical-peptide conjugation in a direct peptide reactivity assay (DPRA), which measures the depletion of two synthetic peptides containing lysine or cysteine residues. To improve assay throughput, sensitivity and accuracy, an automated 384-well plate-based RapidFire solid-phase extraction (SPE) system coupled with tandem mass spectrometry (MS/MS) DPRA was developed and validated in the presence of a newly designed internal standard. Compared to the HPLC/UV-based DPRA, the automated SPE-MS/MS-based DPRA improved throughput from 16 min to 10 s per sample, and substrate peptides usage was reduced from 100 mM to 5 mu M. When implementing the SPE-MS/MS-based DPRA into a high-throughput platform, we found 10 compounds that depleted lysine peptide and 24 compounds that depleted cysteine peptide (including 7 unreported chemicals from 55 compounds we tested) in a concentration-response manner. The adduct formation between cysteine and cinnamic aldehyde and ethylene glycol dimethacrylate were further analyzed using high-performance liquid chromatography time-of-flight mass spectrometry (HPLC-TOF-MS) to confirm the conjugation. Overall, the automated SPE-MS/MS-based platform is an efficient, economic, and accurate way to detect skin sensitizers. (C) 2020 Published by Elsevier B.V.
引用
收藏
页码:67 / 77
页数:11
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