从铜绿微囊藻 K-139 中分离得到的化合物对 FVIIa-sTF 和凝血酶的抑制活性。

FVIIa-sTF and Thrombin Inhibitory Activities of Compounds Isolated from Microcystis aeruginosa K-139.

机构信息

Faculty of Pharmacy, Meijo University, Tempaku, Nagoya 468-8503, Japan.

College of Agriculture, Ibaraki University, Ami, Ibaraki 300-0393, Japan.

出版信息

Mar Drugs. 2017 Aug 30;15(9):275. doi: 10.3390/md15090275.

DOI:10.3390/md15090275

PMID:28867804

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5618414/

Abstract

The rise of bleeding and bleeding complications caused by oral anticoagulant use are serious problems nowadays. Strategies that block the initiation step in blood coagulation involving activated factor VII-tissue factor (fVIIa-TF) have been considered. This study explores toxic K-139, from Lake Kasumigaura, Ibaraki, Japan, as a promising cyanobacterium for isolation of fVIIa-sTF inhibitors. K-139 underwent reversed-phase solid-phase extraction (ODS-SPE) from 20% MeOH to MeOH elution with 40%-MeOH increments, which afforded aeruginosin K-139 in the 60% MeOH fraction; micropeptin K-139 and microviridin B in the MeOH fraction. Aeruginosin K-139 displayed an fVIIa-sTF inhibitory activity of ~166 µM, within a 95% confidence interval. Micropeptin K-139 inhibited fVIIa-sTF with EC 10.62 µM, which was more efficient than thrombin inhibition of EC 26.94 µM. The thrombin/fVIIa-sTF ratio of 2.54 in micropeptin K-139 is higher than those in 4-amidinophenylmethane sulfonyl fluoride (APMSF) and leupeptin, when used as positive controls. This study proves that K-139 is a new source of fVIIa-sTF inhibitors. It also opens a new avenue for micropeptin K-139 and related depsipeptides as fVIIa-sTF inhibitors.

摘要

目前，口服抗凝剂使用引起的出血和出血并发症的增加是一个严重的问题。人们已经考虑了阻断涉及激活的因子 VII-组织因子（fVIIa-TF）的凝血起始步骤的策略。本研究探索了来自日本茨城县霞浦湖的有毒 K-139，作为分离 fVIIa-TF 抑制剂的有前途的蓝藻。K-139 经过反相固相萃取（ODS-SPE），用 40%甲醇进行梯度洗脱，从 20%甲醇中洗脱，在 60%甲醇级分中获得绿脓菌素 K-139；在甲醇级分中获得微缩肽 K-139 和微菌素 B。绿脓菌素 K-139 显示出约 166µM 的 fVIIa-TF 抑制活性，置信区间为 95%。微缩肽 K-139 抑制 fVIIa-TF 的 EC10.62µM，比凝血酶抑制 EC26.94µM更有效。微缩肽 K-139 的凝血酶/fVIIa-TF 比值为 2.54，高于用作阳性对照的 4-氨基苯甲脒磺酰氟（APMSF）和亮抑酶肽。本研究证明 K-139 是 fVIIa-TF 抑制剂的新来源。它还为微缩肽 K-139 和相关的 depsipeptides 作为 fVIIa-TF 抑制剂开辟了新途径。