Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro

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., and Craik, David J. (2014) Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro. Chemistry & Biology, 21 (2). pp. 284-294.

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Abstract

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 (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.

Item ID: 34644
Item Type: Article (Research - C1)
ISSN: 1879-1301
Funders: Australian Research Council (ARC), Queensland Government Department of Science, Information Technology, Innovation and the Arts Co-investment Fund, Pfizer, Inc., National Health and Medical Research Council (NHMRC)
Projects and Grants: ARC Linkage grant LP110200213, NHRMC APP1026501
Date Deposited: 27 Aug 2014 01:14
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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