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Issue 47, 2013
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Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

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Abstract

The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg1-Arg2-2-Nal3-Gly4-D-Tyr5-), 2; 2-Nal = 3-(2-naphthyl)alanine) 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. While the structure–activity relationships for Arg1, Arg2, and Gly4 are well established, less is understood about the roles of the aromatic residues 2-Nal3 and D-Tyr5. Here we report further structure–activity relationship studies of these two positions, which showed that (i) the distal aromatic ring of the 2-Nal3 side chain is required in order to maintain high potency and (ii) replacement of D-Tyr5 with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr5 was only 13-fold less potent than 2, which means that the D-Tyr5 side chain is dispensable. These findings were rationalized based on molecular docking, and the collective structure–activity data for the cyclopentapeptides suggest that appropriately designed Arg2-2-Nal3 dipeptidomimetics have potential as CXCR4 antagonists.

Graphical abstract: Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

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Publication details

The article was received on 19 Jun 2013, accepted on 04 Oct 2013 and first published on 07 Oct 2013


Article type: Paper
DOI: 10.1039/C3OB41941J
Citation: Org. Biomol. Chem., 2013,11, 8202-8208
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    Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

    J. Mungalpara, Z. G. Zachariassen, S. Thiele, M. M. Rosenkilde and J. Våbenø, Org. Biomol. Chem., 2013, 11, 8202
    DOI: 10.1039/C3OB41941J

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