Issue 10, 2013

A new approach to inhibit human β-tryptase by protein surface binding of four-armed peptide ligands with two different sets of arms

Abstract

A series of six new tetravalent ligands (1–6) with two different sets of arms bind to the surface of β-tryptase, a tetrameric enzyme with an A2B2 arrangement of its four monomers and two different binding sites on its protein surface (as suggested by a docking study). Besides proteinogenic amino acids also the guanidiniocarbonyl pyrrole cation (abbreviated as GCP), as an artificial arginine analog, was introduced into the arms of the ligands to investigate its influence on protein surface binding and enzyme inhibition. Furthermore, four ligands (7–10) with four identical arms also containing the GCP group were additionally synthesized to study the influence of the GCP moiety on the inhibition properties compared to related ligands previously identified by us in earlier work. The best ligand from this new series (RWKG)2(GCP-LFG)2 (6) indeed contains the artificial GCP group and with a Ki-value of 67 nM is two orders of magnitude more efficient than the analogous ligand (RWKG)2(RLFG)2 (1) derived solely from proteinogenic amino acids. Hence, four-armed ligands with two different arms are indeed efficient inhibitors for β-tryptase and the artificial GCP group can improve the binding affinity of this type of ligand to the protein, demonstrating the advantage of tailor-made binding motifs to increase affinity.

Graphical abstract: A new approach to inhibit human β-tryptase by protein surface binding of four-armed peptide ligands with two different sets of arms

Supplementary files

Article information

Article type
Paper
Submitted
27 Nov 2012
Accepted
22 Jan 2013
First published
22 Jan 2013

Org. Biomol. Chem., 2013,11, 1631-1639

A new approach to inhibit human β-tryptase by protein surface binding of four-armed peptide ligands with two different sets of arms

Q. Jiang, L. Bartsch, W. Sicking, P. R. Wich, D. Heider, D. Hoffmann and C. Schmuck, Org. Biomol. Chem., 2013, 11, 1631 DOI: 10.1039/C3OB27302D

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements