کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1393658 | 983966 | 2014 | 11 صفحه PDF | دانلود رایگان |
• Structure-based design was used to identify inhibitors of the PCSK9/LDL-R complex
• Small EGF-A-based inhibitors of PCSK9 were identified based on rational design
• The peptides retained binding affinity as well as functional activity for PCSK9
• The structure of an EGF-A-based inhibitor was determined in complex with PCSK9
SummaryDisrupting 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 (KD = 0.6 μM) compared with wild-type EGF-A (KD = 1.2 μM), and the ability to increase LDL-R recycling in the presence of PCSK9 in a cell-based assay.
Journal: - Volume 21, Issue 2, 20 February 2014, Pages 284–294