Synthesis and SAR of a Library of Cell-Permeable Biotin-R8ERY* Peptidomimetics Inhibiting α4β7 Integrin Mediated Adhesion of TK-1 Cells to MAdCAM-1-Fc
Stefanie Papst A , Anaïs F. M. Noisier A , Margaret A. Brimble A C , Yi Yang B , Yih-Chih Chan B and Geoffrey W. Krissansen B
+ Author Affiliations
- Author Affiliations
A School of Chemical Sciences, The University of Auckland, Auckland Central 1010, New Zealand.
B Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland Central 1010, New Zealand.
C Corresponding author. Email: m.brimble@auckland.ac.nz
Australian Journal of Chemistry 65(9) 1349-1358 https://doi.org/10.1071/CH12227
Submitted: 2 May 2012 Accepted: 18 July 2012 Published: 15 August 2012
Abstract
The α4β7 integrin is a well‐known target for the development of drugs against various inflammatory disease states including inflammatory bowel disease, type 1 diabetes, and multiple sclerosis. The β7 subunit contains the cell adhesion regulatory domain (CARD) motif YDRREY within its cytoplasmic domain, which is an effective peptide agent for inhibiting T-cell adhesion. The synthesis of a library of cell-permeable β7 integrin inhibitors based on the shortened biotin-R8ERY (R8 = (l-arginine)8) motif is reported, wherein the tyrosine residue has been modified. The synthesised peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn2+-activated adhesion of mouse TK-1 T-cells to mouse MAdCAM-1. Several analogues exhibited improved activity to that of the tyrosine-containing lead compound 1 (biotin-R8ERY). Specifically, analogues 4, 10, and 22 bearing a 4-chloro, a 4-nitro, and a 3,3-diphenyl substituent showed an increase in activity of approximately two-fold compared with that of the initial lead compound. The six most active compounds of the tested series had IC50’s between 25 and 50 μM.
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