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

Salvatore Di Maro, Anna Maria Trotta, Diego Brancaccio, Francesco Saverio Di Leva, Valeria La Pietra, Caterina Ieranò, Maria Napolitano, Luigi Portella, Crescenzo D'Alterio, Rosa Anna Siciliano, Deborah Sementa, Stefano Tomassi, Alfonso Carotenuto, Ettore Novellino, Stefania Scala, Luciana Marinelli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)8369-8380
Number of pages12
JournalJournal of Medicinal Chemistry
Volume59
Issue number18
DOIs
Publication statusPublished - Sep 22 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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