TY - JOUR
T1 - Peptides targeting chemokine receptor CXCR4
T2 - Structural behavior and biological binding studies
AU - Costantini, Susan
AU - Raucci, Raffaele
AU - Colonna, Giovanni
AU - Mercurio, Flavia Anna
AU - Trotta, Anna Maria
AU - Paola, Ringhieri
AU - Leone, Marilisa
AU - Rossi, Filomena
AU - Pellegrino, Carmela
AU - Castello, Giuseppe
AU - Scala, Stefania
PY - 2014
Y1 - 2014
N2 - CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. CXCL12/CXCR4 axis plays a central role in diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis, and lupus and, hence, indicated as putative therapeutic target. Although multiple CXCR4 antagonists have been developed, there is only one marketed drug, plerixafor, indicated for stem cell mobilization in poor mobilizer patients. In this work, we have designed and synthesized two peptides, six and seven residues long, using as template the N-terminal region of CXCL12; analyzed their conformations by CD, NMR, and molecular dynamics simulations; simulated their complexes with CXCR4 by docking methods; and validated these data by in vitro studies. The results showed that the two peptides are rather flexible in aqueous solution lacking ordered secondary structure elements and present a promising affinity for CXCR4. This affinity is not revealed for CXCR7, indicating a specificity for CXCR4.
AB - CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. CXCL12/CXCR4 axis plays a central role in diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis, and lupus and, hence, indicated as putative therapeutic target. Although multiple CXCR4 antagonists have been developed, there is only one marketed drug, plerixafor, indicated for stem cell mobilization in poor mobilizer patients. In this work, we have designed and synthesized two peptides, six and seven residues long, using as template the N-terminal region of CXCL12; analyzed their conformations by CD, NMR, and molecular dynamics simulations; simulated their complexes with CXCR4 by docking methods; and validated these data by in vitro studies. The results showed that the two peptides are rather flexible in aqueous solution lacking ordered secondary structure elements and present a promising affinity for CXCR4. This affinity is not revealed for CXCR7, indicating a specificity for CXCR4.
KW - antagonists
KW - cancer
KW - CXC chemokines
KW - CXCR4
KW - inflammation
KW - molecular docking
KW - molecular dynamics
KW - molecular recognition
KW - NMR
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U2 - 10.1002/psc.2614
DO - 10.1002/psc.2614
M3 - Article
C2 - 24474664
AN - SCOPUS:84896111950
VL - 20
SP - 270
EP - 278
JO - Journal of Peptide Science
JF - Journal of Peptide Science
SN - 1075-2617
IS - 4
ER -