title: Exploring the N-Terminal Region of C-X-C Motif Chemokine 12 (CXCL12): Identification of Plasma-Stable Cyclic Peptides As Novel, Potent C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonists.
abstract: We previously reported the discovery of a CXCL12-mimetic cyclic peptide (2) as a selective CXCR4 antagonist showing promising in vitro and in vivo anticancer activity. However, further development of this peptide was hampered by its degradation in biological fluids as well as by its low micromolar affinity for the receptor. Herein, extensive chemical modifications led to the development of a new analogue (10) with enhanced potency, specificity, and plasma stability. A combined approach of Ala-amino acid scan, NMR, and molecular modeling unraveled the reasons behind the improved binding properties of 10 vs 2. Biological investigations on leukemia (CEM) and colon (HT29 and HCT116) cancer cell lines showed that 10 is able to impair CXCL12-mediated cell migration, ERK-phosphorylation, and CXCR4 internalization. These outcomes might pave the way for the future preclinical development of 10 in CXCR4 overexpressing leukemia and colon cancer.
authors: DiSTABiF, Second University of Naples , Via Vivaldi 43, 81100 Caserta, Italy.
authors: Salvatore
authors: S
authors: Di Maro
authors: Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale", IRCCS-ITALY , Via M. Semmola, 80131 Naples, Italy.
authors: Anna Maria
authors: AM
authors: Trotta
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.|Laboratory of Food Chemistry, Dipartimento di Agraria (QuaSic.A.Tec.), Università Mediterranea di Reggio Calabria , Reggio Calabria, loc. Feo di Vito, 89122 Reggio Calabria, Italy.
authors: Diego
authors: D
authors: Brancaccio
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
authors: Francesco Saverio
authors: FS
authors: Di Leva
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
authors: Valeria
authors: V
authors: La Pietra
authors: Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale", IRCCS-ITALY , Via M. Semmola, 80131 Naples, Italy.
authors: Caterina
authors: C
authors: Ieranò
authors: Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale", IRCCS-ITALY , Via M. Semmola, 80131 Naples, Italy.
authors: Maria
authors: M
authors: Napolitano
authors: Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale", IRCCS-ITALY , Via M. Semmola, 80131 Naples, Italy.
authors: Luigi
authors: L
authors: Portella
authors: Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale", IRCCS-ITALY , Via M. Semmola, 80131 Naples, Italy.
authors: Crescenzo
authors: C
authors: D'Alterio
authors: Istituto di Scienze dell'Alimentazione, CNR , Via Roma 64, 83100 Avellino, Italy.
authors: Rosa Anna
authors: RA
authors: Siciliano
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
authors: Deborah
authors: D
authors: Sementa
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
authors: Stefano
authors: S
authors: Tomassi
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
authors: Alfonso
authors: A
authors: Carotenuto
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
authors: Ettore
authors: E
authors: Novellino
authors: Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale", IRCCS-ITALY , Via M. Semmola, 80131 Naples, Italy.
authors: Stefania
authors: S
authors: Scala
authors: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
authors: Luciana
authors: L
authors: Marinelli
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000737:chemistry* / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4