5LFF

NMR structure of peptide 2 targeting CXCR4

Summary for 5LFF

• Entry DOI: 10.2210/pdb5lff/pdb
• NMR Information: BMRB: 34016
• Descriptor: ARG-ALA-CYS-ARG-PHE-PHE-CYS (1 entity in total)
• Functional Keywords: cxcr4, cxcl12, cxcr4 antagonists, cancer, molecular invasion, drug design, chemokine, cytokine
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 904.11

Authors

Di Maro, S.,Trotta, A.M.,Brancaccio, D.,Di Leva, F.S.,La Pietra, V.,Ierano, C.,Napolitano, M.,Portella, L.,D'Alterio, C.,Siciliano, R.A.,Sementa, D.,Tomassi, S.,Carotenuto, A.,Novellino, E.,Scala, S.,Marinelli, L. (deposition date: 2016-07-01, release date: 2016-09-07, Last modification date: 2024-10-09)

Primary citation

Di Maro, S.,Trotta, A.M.,Brancaccio, D.,Di Leva, F.S.,La Pietra, V.,Ierano, C.,Napolitano, M.,Portella, L.,D'Alterio, C.,Siciliano, R.A.,Sementa, D.,Tomassi, S.,Carotenuto, A.,Novellino, E.,Scala, S.,Marinelli, L.
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.
J.Med.Chem., 59:8369-8380, 2016

PubMed 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.

PubMed: 27571038
DOI: 10.1021/acs.jmedchem.6b00695

Experimental method

SOLUTION NMR