Huang_2020_J.Med.Chem_63_7052

Reference

Title : Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach - Huang_2020_J.Med.Chem_63_7052
Author(s) : 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
Ref : Journal of Medicinal Chemistry , 63 :7052 , 2020
Abstract : 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.
ESTHER : Huang_2020_J.Med.Chem_63_7052
PubMedSearch : Huang_2020_J.Med.Chem_63_7052
PubMedID: 32459096
Gene_locus related to this paper: human-PLA2G7

Related information

Gene_locus related to this paper: human-PLA2G7

Citations formats

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 (2020)
Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach
Journal of Medicinal Chemistry 63 :7052

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 (2020)
Journal of Medicinal Chemistry 63 :7052