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Evaluation of the metabolism of PEP06,an endostatin-RGDRGD 30-amino-acid polypeptide and a promising novel drug for targeting tumor cells

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Journal of Pharmaceutical Analysis 2022年第5期12卷 766-773页

作者： Liyun Niu Huiyu Zhou Yueru Lian Ya Gao Yulu Liu Ruolan Gu Zhuona Wu Xiaoxia Zhu Hui Gan Zhiyun Meng Guifang Dou State Key Laboratory of Drug Metabolism and Pharmacokinetics Department of Pharmaceutical SciencesBeijing Institute of Radiation MedicineBeijing100850China Henan University KaifengHenan475004China

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp(RGDRGD)30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N terminus.The active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral effect.However,little is known about the kinetics and degradation products of PEP06 in vitro or in vivo.In this study,we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species;we further identified the degradation characteristics of its cleavage products.PEP06 underwent rapid enzymatic degradation in multiple types of living cells,and the liver,kidney,and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of PEP06.We identified metabolites of PEP06 using full-scan mass spectrometry(MS)and tandem MS(MS2),wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide,formed by successive losses of amino acids.The metabolites were C and N terminal truncated products of PEP06.The structures of 11 metabolites(M6,M7,M16,M17,M21,M25,M33,M34,M39,M40,and M42)were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized metabolites.We have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06,which can support further drug research.

关键词： PEP06 HRMS Metabolic stability metabolites identification

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质谱研究砷的形态及结合蛋白（英文）

质谱研究砷的形态及结合蛋白（英文）

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第三届全国质谱分析学术报告会

作者： Xiaowen Yan Hanyong Peng Aleksandra Popowich Qingqing Liu Xiufen Lu Xing-Fang Li William R.Cullen Michael Weinfeld 乐晓春 Division of Analytical and Environmental Toxicology Faculty of Medicine and Dentistry University of Alberta

This presentation will highlight recent advances in mass spectrometry studies of arsenic species and their binding to proteins. High performance liquid chromatography（HPLC） separation and simultaneous detection with both inductively coupled plasma mass spectrometry（ICPMS） and electrospray ionization tandem mass spectrometry（ESI-MS/MS） enabled identification and quantitation of individual arsenic species present in various environmental samples. Synthesis of arsenic standards helped facilitate identification of new arsenic metabolites. The use of high resolution mass spectrometry further supported the identification of previously "unknown" arsenic species. Binding of arsenic to the promyelocytic leukemia fusion protein（oncoprotein） is a key event of the successful treatment of acute promyelocytic leukemia（APL） Therefore, identification of other arsenic-binding proteins is important for developing arsenic-based therapeutics for other cancers. We describe a strategy for the capture and identification of arsenic-binding proteins in living cells. An affinity capture technique, using click chemistry and mass spectrometry, enabled identification of arsenic-binding proteins in human cell lines. Applications of the technique are demonstrated using the A549 human lung carcinoma cells. We are able to capture and identify 48 arsenic-binding proteins in A549 cells. Among the identified proteins are several antioxidant proteins（e.g., thioredoxin, peroxiredoxin, peroxide reductase, glutathione reductase, and protein disulfide isomerase） and glyceraldehyde-3-phosphate dehydrogenase. Studies of arsenic binding to some of these proteins and the consequent enzymatic inhibition suggest that these proteins could be potential molecular targets that play important roles in cancer treatment and in arsenic-induced health effects. These two examples, identification of arsenic metabolites and characterization of protein binding, demonstrate importance of mass spectrometry techniques.

关键词： arsenic targeted proteomics metabolites identification protein binding LC-MS

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