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Discovery and Characterization of a Potent and Specific Peptide Ligand Targeting
Endothelial Progenitor Cells and Endothelial Cells for Tissue Regeneration
#MMPMID28195700
Hao D
; Xiao W
; Liu R
; Kumar P
; Li Y
; Zhou P
; Guo F
; Farmer DL
; Lam KS
; Wang F
; Wang A
ACS Chem Biol
2017[Apr]; 12
(4
): 1075-1086
PMID28195700
show ga
Endothelial progenitor cells (EPCs) and endothelial cells (ECs) play a vital role
in endothelialization and vascularization for tissue regeneration. Various EPC/EC
targeting biomolecules have been investigated to improve tissue regeneration with
limited success often due to their limited functional specificity and structural
stability. One-bead one-compound (OBOC) combinatorial technology is an ultrahigh
throughput chemical library synthesis and screening method suitable for ligand
discovery against a wide range of biological targets, such as integrins. In this
study, using primary human EPCs/ECs as living probes, we identified an ?v?3
integrin ligand LXW7 discovered by OBOC combinatorial technology as a potent and
specific EPC/EC targeting ligand. LXW7 overcomes the major barriers of other
functional biomolecules that have previously been used to improve vascularization
for tissue regeneration and possesses optimal stability, EPC/EC specificity, and
functionality. LXW7 is a disulfide cyclic octa-peptide (cGRGDdvc) containing
unnatural amino acids flanking both sides of the main functional motif; therefore
it will be more resistant to proteolysis and more stable in vivo compared to
linear peptides and peptides consisting of only natural amino acids. Compared
with the conventional ?v?3 integrin ligand GRGD peptide, LXW7 showed stronger
binding affinity to primary EPCs/ECs but weaker binding to platelets and no
binding to THP-1 monocytes. In addition, ECs bound to the LXW7 treated culture
surface exhibited enhanced biological functions such as proliferation, likely due
to increased phosphorylation of VEGF receptor 2 (VEGF-R2) and activation of
mitogen-activated protein kinase (MAPK) ERK1/2. Surface modification of
electrospun microfibrous PLLA/PCL biomaterial scaffolds with LXW7 via Click
chemistry resulted in significantly improved endothelial coverage. LXW7 and its
derivatives hold great promise for EPC/EC recruitment and delivery and can be
widely applied to functionalize various biological and medical materials to
improve endothelialization and vascularization for tissue regeneration
applications.
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