Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro.
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.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Christina I
CI
Schroeder
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Joakim E
JE
Swedberg
Structural Biology and Biophysics, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Jane M
JM
Withka
School of Biomedical Sciences, The University of Queensland, Brisbane, 4072 QLD, Australia.
K Johan
KJ
Rosengren
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Muharrem
M
Akcan
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Daniel J
DJ
Clayton
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Norelle L
NL
Daly
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Olivier
O
Cheneval
Structural Biology and Biophysics, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Kris A
KA
Borzilleri
Structural Biology and Biophysics, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Matt
M
Griffor
PDM-NCE, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Ingrid
I
Stock
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Barbara
B
Colless
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Phillip
P
Walsh
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia.
Philip
P
Sunderland
CVMED, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.
Allan
A
Reyes
CVMED, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.
Robert
R
Dullea
Structural Biology and Biophysics, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Mark
M
Ammirati
Structural Biology and Biophysics, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Shenping
S
Liu
CVMED, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.
Kim F
KF
McClure
CVMED, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.
Meihua
M
Tu
CVMED, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.
Samit K
SK
Bhattacharya
CVMED, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.
Spiros
S
Liras
CVMED, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.
David A
DA
Price
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072 QLD, Australia. Electronic address: d.craik@imb.uq.edu.au.
David J
DJ
Craik
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D010455:Peptides; D011973:Receptors, LDL; D004815:Epidermal Growth Factor; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases