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Searches for lead compounds intended for prevention of infective endocarditis by means of combinatorial chemical libraries.

通过组合化学库搜索用于预防感染性心内膜炎的先导化合物。

基本信息

批准号：
12557187
负责人：
INOUE Masakazu
金额：
$ 7.04万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Infective endocarditis is often caused by oral indigenous bacteria introduced into the blood stream. Abnormal or damaged heart valves including artificial valves are the most susceptible to the infection, while normal valves can be infected only by some aggressive bacteria when present in large numbers. The ability of bacteria to adhere to extracellular matrix proteins, which are exposed at the wound endocardia, is considered critical for infection. An oral viridans streptococcus, Granulicatella (Abiotrophia) adiacens, often induces endocarditis and the pathogenicity is related to its adhering activities to fibronectin (Fn). The purpose of our present study is the development of candidate compounds, which can interfere with the adherence of the microorganism. First, monoclonal antibodies against Fn were prepared and found to inhibit Fn-binding ability of the organism. On the other hand, random hexapeptide libraries were constructed by the "one peptide on one-bead" approach. A modified libraries, Gly-X1-X2-X3-X4-Gly-Tenta Gel (X = equal mixture of natural amino acids except Cys) were constructed for easier and more rapid identification. The "one peptide on one-bead" strategy is however limited to determining epitopes since quantitative evaluation is difficult. We attempted to improve the position scan strategy, in which we did not employ mixture based protocols to construct the library but each of 19 amino acid derivatives is individually coupled in divided resins. In the novel screening methodology, information obtained by use of the two types of peptide libraries supplement each other. It will not only facilitate identification of lead compounds for prevention of infective endocarditis, but also improve the efficiency in search for low molecular weight compounds that mimic interactions of higher molecular weight biological substances.

感染性心内膜炎通常是由口腔本土细菌进入血流引起的。包括人工瓣膜在内的异常或受损的心脏瓣膜最容易受到感染，而正常的瓣膜只有在大量存在时才会被一些侵袭性细菌感染。细菌附着于细胞外基质蛋白的能力被认为是感染的关键，这些蛋白暴露在伤口的心内膜上。绿色链球菌是一种口腔绿色链球菌，常引起心内膜炎，其致病机制与其与纤维连接蛋白(FN)的黏附活性有关。我们目前的研究目的是开发能够干扰微生物黏附的候选化合物。首先，制备了抗FN的单抗，发现其抑制了生物体与FN的结合能力。另一方面，利用“一球一肽”的方法构建了随机六肽文库。为便于快速鉴定，构建了Gly-X1-X2-X3-X4-Gly-Tenta Gel(X=除半胱氨酸外的天然氨基酸的等量混合物)文库。然而，“一珠一肽”策略仅限于确定表位，因为定量评估是困难的。我们试图改进位置扫描策略，在该策略中，我们没有使用基于混合物的方法来构建文库，而是19个氨基酸衍生物中的每一个都单独偶联在分开的树脂中。在新的筛选方法中，通过使用两种类型的肽库获得的信息是相辅相成的。这不仅有助于鉴定预防感染性心内膜炎的先导化合物，而且可以提高寻找模拟较高分子量生物物质相互作用的低分子化合物的效率。