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, Phillip, 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 and Biology, 21 2: 284-294. doi:10.1016/j.chembiol.2013.11.014

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Author 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, Phillip
Reyes, Allan
Dullea, Robert
Ammirati, Mark
Liu, Shenping
McClure, Kim F.
Tu, Meihua
Bhattacharya, Samit K.
Liras, Spiros
Price, David A.
Craik, David J.
Title Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro
Journal name Chemistry and Biology   Check publisher's open access policy
ISSN 1074-5521
Publication date 2014-02-20
Sub-type Article (original research)
DOI 10.1016/j.chembiol.2013.11.014
Open Access Status DOI
Volume 21
Issue 2
Start page 284
End page 294
Total pages 11
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Formatted abstract
• 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

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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biological Sciences Publications
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 8 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 8 times in Scopus Article | Citations
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Created: Tue, 04 Feb 2014, 01:51:35 EST by Susan Allen on behalf of Institute for Molecular Bioscience