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.
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.
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