Mass spectrometry-guided discovery of new analogs of bicyclic phosphotriester salinipostin and evaluation of their monoacylglycerol lipase inhibitory activity
Mass spectrometry-guided discovery of new analogs of bicyclic phosphotriester salinipostin and evaluation of their monoacylglycerol lipase inhibitory activity
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DOI：
10.1093/bbb/zbac131
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发表时间：
2022-08-02
影响因子：
1.6
通讯作者：
Yotsu-Yamashita，Mari
中科院分区：
文献类型：
--
作者：
Kudo，Yuta;Konoki，Keiichi;Yotsu-Yamashita，Mari
含有极不寻常的磷酸三酯环的天然产物被认为是有效的丝氨酸水解酶抑制剂。从海洋放线菌salinispora中提取的长链双环烯醇-磷酸三酯盐碱肽（SPTs）已被确定为选择性抗疟药。基于其与放线菌信号分子的结构关系以及在放线菌中普遍存在的spt样生物合成基因簇，已经提出了磷三酯的潜在调节功能。在这项研究中，我们建立了一种质谱引导的筛选方法，重点是磷酸三酯的特征片段离子。将该筛选方法应用于SPT产生物salinispora tropicaCNB-440，发现了新的SPT类似物（4-6），并通过光谱分析对其结构进行了鉴定。先前已知的和本文鉴定的SPT类似物在纳摩尔范围内抑制人单酰基甘油脂肪酶（MAGL）的活性，MAGL是内源性大麻素系统中的关键丝氨酸水解酶。该方法可应用于磷酸三酯、潜在丝氨酸水解酶抑制剂和信号分子的筛选。
Natural products containing the highly unusual phosphotriester ring are known to be potent serine hydrolase inhibitors. The long-chain bicyclic enol-phosphotriester salinipostins (SPTs) from the marine actinomyceteSalinisporahave been identified as selective antimalarial agents. A potential regulatory function has been suggested for phosphotriesters based on their structural relationship with actinomycete signaling molecules and the prevalence ofspt-like biosynthetic gene clusters across actinomycetes. In this study, we established a mass spectrometry–guided screening method for phosphotriesters focusing on their characteristic fragment ions. Applying this screening method to the SPT producerSalinispora tropicaCNB-440, new SPT analogs (4-6) were discovered and their structures were elucidated by spectroscopic analyses. Previously known and herein-identified SPT analogs inhibited the activity of human monoacylglycerol lipase (MAGL), a key serine hydrolase in the endocannabinoid system, in the nanomolar range. Our method could be applied to the screening of phosphotriesters, potential serine hydrolase inhibitors and signaling molecules.