Function of FC 131 as CXCR4 antagonists



The cyclopentapeptide FC 131 (cyclo(-L-Arg1-L-Arg2-L-2-Nal3-Gly4-D-Tyr5-), 2-Nal=3-(2-naphthyl) alanine)) is an antagonist for CXC-chemokine receptor 4 (CXCR4), which plays a role in HIV-infection, cancer and stem cell recruitment. FC 131 was identified from a cyclic-pentapeptide library whose design was based on structure-activity relationship (SAR) studies of T140 analogues, and it displays nanomolar affinity and potency at CXCR4 and serves as lead compound for development of more drug-like peptidomimetic CXCR4 antagonists.

Biological Activity

The chemokine receptors are a subfamily of G-protein coupled receptors (GPCRs) that bind to chemokines, a family of chemotactic factor proteins. One chemokine receptor, CXCR4, binds CXCL12 (SDF-1a, stromal cell derived factor 1a), which engages the leukocyte chemotaxis in the immune system, progenitor cell migration, embryonic development of the cardiovascular, hemopoietic and central nervous systems. SAR studies of FC 131 have shown that The D-Tyr1-Arg2 substructure in FC 131 is therefore involved in direct or indirect contributions to binding with CXCR4, which is a crucial functionality and minor modifications abolish activity. The aromatic residues in position 3 (2-Nal3) and 5 (D-Tyr5) are also important for proper function. Importantly, position 3 requires conservation as 2-Nal while position 5 allows for some modifications.


FC 131 represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation, and autoimmune diseases.


1. Yasushi Yoshikawa, Kazuya Kobayashi, Shinya Oishi, Nobutaka Fujii, Toshio Furuya. Molecular modeling study of cyclic pentapeptide CXCR4 antagonists: New insight into CXCR4–FC131 interactions. Bioorg. Med. Chem. Lett. 2012, 22, 2146-2150.

2. S Thiele1, J Mungalpara, A Steen, M M Rosenkilde, J Våbenø. Determination of the binding mode for the cyclopentapeptide CXCR4 antagonist FC131 using a dual approach of ligand modifications and receptor mutagenesis. British Journal of Pharmacology, 2014, 171 (23), 5313-5329.

3. Kazuya Kobayashi, Shinya Oishi, Ryoko Hayashi, Kenji Tomita, Tatsuhiko Kubo, Noriko Tanahara, Hiroaki Ohno, Yasushi Yoshikawa, Toshio Furuya, Masaru Hoshino, Nobutaka Fujii. Structure-Activity Relationship Study of a CXC Chemokine Receptor Type 4 Antagonist, FC131, Using a Series of Alkene Dipeptide Isosteres. J. Med. Chem. 2012, 55, 2746-2757.

4. Jignesh Mungalpara, Zack G. Zachariassen, Stefanie Thiele, Mette M. Rosenkilde, Jon Våbenø. Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists. Org. Biomol. Chem., 2013, 11, 8202-8208.

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