title: Nanomolar E-selectin antagonists with prolonged half-lives by a fragment-based approach.
abstract: 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 carbohydrate-lectin complexes with typical half-lives (t(1/2)) in the range of one second or even less, these fragment-based selectin antagonists show t1/2 of several minutes. They exhibit a promising starting point for the development of novel anti-inflammatory drugs.
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Jonas
authors.initials: J
authors.lastname: Egger
authors.forename: Céline
authors.initials: C
authors.lastname: Weckerle
authors.forename: Brian
authors.initials: B
authors.lastname: Cutting
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.forename: Said
authors.initials: S
authors.lastname: Rabbani
authors.forename: Katrin
authors.initials: K
authors.lastname: Lemme
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D019040:E-Selectin / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular
chemical_list: D019040:E-Selectin