Nanomolar E‑Selectin Antagonists with Prolonged Half-Lives by a Fragment-Based Approach

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 <i>K</i>_D values ranging from 30 to 89 nM. In contrast to carbohydrate–lectin complexes with typical half-lives (<i>t</i>_1/2) in the range of one second or even less, these fragment-based selectin antagonists show <i>t</i>_1/2 of several minutes. They exhibit a promising starting point for the development of novel anti-inflammatory drugs