Peptides targeting chemokine receptor CXCR4: structural behavior and biological binding studies.
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.
Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale' (IRCCS), Naples, Italy.
Susan
S
Costantini
Raffaele
R
Raucci
Giovanni
G
Colonna
Flavia Anna
FA
Mercurio
Anna Maria
AM
Trotta
Ringhieri
R
Paola
Marilisa
M
Leone
Filomena
F
Rossi
Carmela
C
Pellegrino
Giuseppe
G
Castello
Stefania
S
Scala
D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D019718:Receptors, CXCR4 / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
C527276:CXCR4 protein, human; D010455:Peptides; D019718:Receptors, CXCR4
CXC chemokines; CXCR4; NMR; antagonists; cancer; inflammation; molecular docking; molecular dynamics; molecular recognition