Design and Synthesis of Truncated EGF-A Peptides that Restore LDL-R Recycling in the Presence of PCSK9 In Vitro

作者：Schroeder Christina I; Swedberg Joakim E; Withka Jane M; Rosengren K Johan; Akcan Muharrem; Clayton Daniel J; Daly Norelle L; Cheneval Olivier; Borzilleri Kris A; Griffor Matt; Stock Ingrid; Colless Barbara; Walsh Phillip; Sunderland Philip; Reyes Allan; Dullea Robert; Ammirati Mark; Liu Shenping; McClure Kim F; Tu Meihua; Bhattacharya Samit K; Liras Spiros; Price David A; Craik David J^*

来源：Chemistry & Biology, 2014, 21(2): 284-294.

DOI：10.1016/j.chembiol.2013.11.014

Disrupting the binding interaction between proprotein convertase (PCSK9) and the epidermal growth factor-like domain A (EGF-A domain) in the low-density lipoprotein receptor (LDL-R) is a promising strategy to promote LDL-R recycling and thereby lower circulating cholesterol levels. In this study, truncated 26 amino acid EGF-A analogs were designed and synthesized, and their structures were analyzed in solution and in complex with PCSK9. The most potent peptide had an increased binding affinity for PCSK9 (K-D = 0.6 mu M) compared with wild-type EGF-A (K-D = 1.2 mu M), and the ability to increase LDL-R recycling in the presence of PCSK9 in a cell-based assay.

• 出版日期2014-2-20