6m08

Publication Abstract from PubMed

Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.

Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach.,Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y, Gao J, Liu Y, Zhou H, Huang R, Li M, Shen J, Xu Y J Med Chem. 2020 Jul 9;63(13):7052-7065. doi: 10.1021/acs.jmedchem.0c00372. Epub , 2020 Jun 10. PMID:32459096^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.