FC 131 is an antagonist of CXCR4 with anti-HIV activity
CAT No: 10-101-256
CAS No:606968-52-9
Synonyms/Alias:FC131;606968-52-9;FC 131;Cyclo(-D-Tyr-Arg-Arg-Nal-Gly-);2-[3-[(2S,5S,8S,14R)-5-[3-(diaminomethylideneamino)propyl]-14-[(4-hydroxyphenyl)methyl]-8-(naphthalen-2-ylmethyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentazacyclopentadec-2-yl]propyl]guanidine;CHEMBL436283;CHEMBL2180076;Fc-131;Cyclo[2-Nal-Gly-D-Tyr-Arg-Arg];SCHEMBL15987252;CHEBI:183910;GLXC-04293;Cyclo(-Nal-Gly-D-Tyr-Arg-Arg-);HY-P1104;BDBM50166106;BDBM50399002;Cyclo-[2-Nal-Gly-D-Tyr-Arg-Arg];EX-A11275;AKOS040745190;DA-53131;CS-0027759;Cyclo[3-(2-naphthalenyl)-L-alanylglycyl-D-tyrosyl-L-arginyl-L-arginyl];1-[3-[(2S,5S,8S,14R)-5-(3-guanidinopropyl)-14-[(4-hydroxyphenyl)methyl]-8-(2-naphthylmethyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentazacyclopentadec-2-yl]propyl]guanidine;N-{3-[(2S,5S,8S,14R)-5-(3-carbamimidamidopropyl)-14-[(4-hydroxyphenyl)methyl]-8-(naphthalen-2-ylmethyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl]propyl}guanidine;N-{3-[(2S,5S,8S,14R)-5-(3-Guanidino-propyl)-14-(4-hydroxy-benzyl)-8-naphthalen-2-ylmethyl-3,6,9,12,15-pentaoxo-1,4,7,10,13pentaaza-cyclopentadec-2-yl]-propyl}-guanidine;
Chemical Name:cyclo[3-(2-naphthalenyl)-L-alanylglycyl-D-tyrosyl-L-arginyl-L-arginyl]
FC131 is a synthetic cyclic peptide known for its potent and selective antagonism of the chemokine receptor CXCR4. As a structurally optimized peptide, FC131 has become a valuable research tool for probing the mechanisms of chemokine signaling and receptor-ligand interactions within the broader context of immunology, oncology, and cell biology. Its distinctive molecular configuration enables high-affinity binding to CXCR4, making it indispensable for studies that require precise modulation of this receptor's function. The compound's robust selectivity and stability further enhance its utility in controlled experimental settings, where interference from off-target effects must be minimized.
Receptor binding studies: FC131 is widely employed in receptor-ligand binding assays to characterize the affinity and specificity of CXCR4 interactions. By serving as a competitive antagonist, it allows researchers to delineate the binding kinetics of endogenous chemokines such as CXCL12 (SDF-1) and to map the structural determinants critical for receptor activation. These studies are essential for understanding the molecular underpinnings of chemokine-mediated signaling and for validating new CXCR4-targeted ligands or inhibitors.
Signal transduction research: The peptide's ability to selectively inhibit CXCR4 makes it a powerful tool for dissecting downstream signaling pathways. Investigators utilize FC131 to block receptor-mediated activation of G-proteins and subsequent intracellular cascades, such as calcium mobilization, MAPK activation, or PI3K/Akt signaling. By selectively modulating CXCR4, it becomes possible to attribute observed cellular responses directly to this receptor, thereby clarifying the role of CXCR4 in various physiological and pathological processes.
Cell migration and invasion assays: FC131 is frequently incorporated into in vitro models that assess chemokine-driven cell migration, such as transwell assays or wound-healing experiments. By antagonizing CXCR4, the peptide effectively inhibits chemotactic responses to CXCL12, enabling detailed evaluation of the receptor's contribution to cell motility, tissue infiltration, and metastatic potential. These applications are particularly relevant in cancer research and studies of immune cell trafficking, where CXCR4-mediated migration plays a pivotal role.
Peptide drug discovery and development: As a structurally defined CXCR4 antagonist, FC131 serves as a reference compound in the screening and optimization of novel peptide-based inhibitors. Its well-characterized activity profile allows for direct comparison with newly synthesized analogs or small-molecule candidates, supporting structure-activity relationship (SAR) studies and the rational design of next-generation chemokine receptor modulators. The compound's stability and specificity also facilitate its use in high-throughput screening platforms.
Analytical method development: FC131's defined peptide sequence and receptor specificity make it a useful standard for validating analytical techniques such as high-performance liquid chromatography (HPLC), mass spectrometry, and peptide quantification assays. Researchers employ it to optimize separation conditions, calibrate detection methods, and assess assay sensitivity for peptide-based analytes. Its role in analytical method development extends to quality control in peptide synthesis and formulation research, where precise characterization of peptide standards is critical.
The Arg2 and 2‐Nal3 side chains of FC131 interact with residues in TM‐3 (His113, Asp171) and TM‐5 (hydrophobic pocket) respectively. Arg1 forms charge‐charge interactions with Asp187 in ECL‐2, while D‐Tyr5 points to the extracellular side of CXCR4. Furthermore, the backbone of FC131 interacts with the chemokine receptor‐conserved Glu288 via two water molecules. Intriguingly, Tyr116 and Glu288 form a H‐bond in CXCR4 crystal structures and mutation of either residue to Ala abolishes CXCR4 activity.
Determination of the binding mode for the cyclopentapeptide CXCR4 antagonist FC131 using a dual approach of ligand modifications and receptor mutagenesis
Previously, we developed a highly potent CXC chemokine receptor type 4 (CXCR4) antagonist, FC131 [cyclo(-d-Tyr1-Arg2-Arg3-Nal4-Gly5-)], from a library of cyclic pentapeptides consisting of pharmacophore residues of the polyphemusin-II-derived anti-human immunodeficiency virus (HIV) peptide T140. Since this novel scaffold for CXCR4 antagonists was identified, a series of cyclic peptides and peptidomimetics have been designed for potential anti-HIV and antimetastatic agents.
Structure–Activity Relationship Study of a CXC Chemokine Receptor Type 4 Antagonist, FC131, Using a Series of Alkene Dipeptide Isosteres
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