Function and Structure Analyses of Anticoagulant and Vasodilator Isolated from the Salivary Glands of Blood Sucking Insects, and Development of Novel Medicine

吸血昆虫唾液腺抗凝剂和血管扩张剂的功能和结构分析及新药开发

基本信息

批准号：
11557022
负责人：
CHINZEI Yasuo
金额：
$ 8.64万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2002
项目状态：
已结题

项目摘要

The salivary glands of blood sucking insects contain some bio-active substances to control blood coagulation and blood vessel of host animals for assisting a continuous blood feeding. In this study, we searched these bio-active molecules from the glands and analyzed the molecular structure, activity and mode of action to elucidate the biological significance of these molecules, and tried to develop a material for novel medicine.We used two blood sucking insects, Triatoma infestans (Ti) and Anopheles stephensi (As), and the tick, Haemaphisalis bispinosa (Hb) as material animals. We established the data bases of salivary gland EST of these animals, and analyzed 179, 120 and 218 molecules with novel sequences, respectively. We identified 5, 3, and 3 novel bio-active molecules respectively after expression by baculo virus expression system and analysis of activities.'Hamadarin', one of them is isolated and identified from the salivary glands of anopheline mosquito As. We found hamadalin inhibits factor XII of coagulation cascade and high molecular weight kininogen by binding them to the binding sites of these molecules to negative charged surface, and as results inhibits coagulation cascade and generation of bladikinin and therefore inflammation. Hamadalin has a possibility to be a lead molecules developing novel anticoagulant and anti-inflammation drug.

吸血昆虫的唾液腺中含有一些生物活性物质，可以控制宿主动物的血液凝固和血管，以协助持续吸血。在本研究中，我们从腺体中寻找这些生物活性分子，并分析其分子结构、活性和作用方式，以阐明这些分子的生物学意义，并尝试开发新药材料。我们使用了两种吸血昆虫、致病锥蝽(Ti)和斯氏按蚊(As)，以及蜱、双刺血蜱(Hb)作为材料动物。我们建立了这些动物唾液腺EST的数据库，并分别分析了179、120和218个具有新序列的分子。通过杆状病毒表达系统表达并进行活性分析，我们分别鉴定出5、3和3种新型生物活性分子。'Hamadarin'是从按蚊As唾液腺中分离鉴定出的其中之一。我们发现金缕梅甙通过将凝血级联因子 XII 和高分子量激肽原结合到这些分子与带负电表面的结合位点来抑制凝血级联和高分子量激肽原，从而抑制凝血级联和剑激肽的生成，从而抑制炎症。 Hamadalin 有可能成为开发新型抗凝和抗炎药物的先导分子。