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

感染性心内膜炎通常是由口腔内的原生细菌引入血流引起的。异常或受损的心脏瓣膜（包括人工瓣膜）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。细菌粘附于暴露在伤口心内膜的细胞外基质蛋白的能力被认为是感染的关键。一种口腔青绿链球菌，无营养芽胞菌（Granulicatella, Abiotrophia） adiacens，常诱发心内膜炎，其致病性与其对纤维连接蛋白的粘附活性有关。我们目前研究的目的是开发候选化合物，它可以干扰微生物的粘附。首先，制备了Fn单克隆抗体，发现其能抑制生物体的Fn结合能力。另一方面，采用“一肽一头”的方法构建随机六肽文库。构建了Gly-X1-X2-X3-X4-Gly-Tenta Gel （X =除Cys外的天然氨基酸的等量混合物）的修饰文库，使鉴定更容易、更快速。然而，由于定量评估困难，“一肽一头”策略仅限于确定表位。我们试图改进位置扫描策略，其中我们没有采用基于混合物的协议来构建文库，而是将19个氨基酸衍生物中的每一个单独偶联在分开的树脂中。在新的筛选方法中，利用两种类型的肽库获得的信息是相互补充的。这不仅有助于鉴定预防感染性心内膜炎的先导化合物，而且提高了寻找模仿高分子量生物物质相互作用的低分子量化合物的效率。

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.