Nanomolar E-Selectin Antagonists with Prolonged Half-Lives by a Fragment-Based Approach
Nanomolar E-Selectin Antagonists with Prolonged Half-Lives by a Fragment-Based Approach
复制标题
DOI：
10.1021/ja4029582
复制
发表时间：
2013-07-03
影响因子：
15
通讯作者：
Ernst, Beat
中科院分区：
文献类型：
--
作者：
Egger, Jonas;Weckerle, Celine;Ernst, Beat
选择素是一个C型凝集素家族，在炎症性疾病(如哮喘和关节炎)中发挥关键作用。然而，唾液酸基Lewis(X)(SLE(X))是所有生理选择素配体的共同四糖表位，其唯一的毫米级亲和力一直是开发用于治疗应用的选择素拮抗剂的主要障碍。在核磁共振指导下的基于片段的方法中，鉴定了与SLE(X)模拟物非常接近的第二个位点结合的配体。通过不同长度的三氮唑键将模拟的SLE(X)连接到最好的第二位配基上所获得的拮抗剂文库通过表面等离子体共振进行了评估。对五个最有希望的候选人的详细分析显示，K-D值在30到89 NM之间的拮抗剂。与典型半衰期(t(1/2))在一秒或更短范围内的碳水化合物相比，这些基于片段的选择素拮抗剂的半衰期(t(1/2))为几分钟。它们为新型抗炎药物的开发提供了一个良好的起点。
Selectins, a family of C-type lectins, play a key role in inflammatory diseases (e.g., asthma and arthritis). However, the only millimolar affinity of sialyl Lewis(x) (sLe(x)), which is the common tetrasaccharide epitope of all physiological selectin ligands, has been a major obstacle to the development of selectin antagonists for therapeutic applications. In a fragment-based approach guided by NMR, ligands binding to a second site in close proximity to a sLe(x) mimic were identified. A library of antagonists obtained by connecting the sLe(x) mimic to the best second-site ligand via triazole linkers of different lengths was evaluated by surface plasmon resonance. Detailed analysis of the five most promising candidates revealed antagonists with K-D values ranging from 30 to 89 nM. In contrast to carbohydratelectin complexes with typical half-lives (t(1/2)) in the range of one second or even less, these fragment-based selectin antagonists show t(1/2) of several minutes. They exhibit a promising starting point for the development of novel anti-inflammatory drugs.