FC131

The cyclopentapeptide FC131 (cyclo(‐L‐Arg¹‐L‐Arg²‐L‐2‐Nal³‐Gly⁴‐D‐Tyr⁵‐)) is an antagonist at the CXC chemokine receptor CXCR4, which plays a role in human immunodeficiency virus infection, cancer and stem cell recruitment. Binding modes for FC131 in CXCR4 have previously been suggested based on molecular docking guided by structure–activity relationship (SAR) data; however, none of these have been verified by in vitro experiments.   >> Read More

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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