α₄β₇/α₄β₁Dual Integrin Antagonists Block α₄β₇-Dependent Adhesion under Shear Flow

Abstract

The ␣ 4 integrin, ␣ 4 ␤ 7 , plays an important role in recruiting circulating lymphocytes to the gastrointestinal tract, where its ligand mucosal addressin cell adhesion molecule-1 (MAd-CAM-1) is preferentially expressed on high endothelial venules (HEVs). Dual antagonists of ␣ 4 ␤ 1 and

Conformational mAb as a Tool for Integrin Ligand Discovery

“…Mouse anti-human CD29, HUTS-21(PE), isotype control (mouse IgG2a κ PE) clone G155-178 were purchased from BD Biosciences (San Jose, CA) and used according to manufacturer's instructions. 16 was synthesized by Dr. Wei Wang (Department of Chemistry, University of New Mexico). Two recently identifi ed VLA-4 ligands 3-(adamantane-1-carbonylamino)-3-(4-ethoxyphenyl) propanoic acid and 3-(adamantane-1-carbonylamino)-3-(4-propoxyphenyl) propanoic acid (SID: 14732971, CID: 5197400; and SID: 14732972, CID: 4329131) were from NIH molecular libraries small molecule repository (NIH MLSMR) (http://pubchem.ncbi.nlm.nih.gov/) curated by BioFocus/ DPI (South San Francisco, CA).…”

“…2C) is described in the literature as a potent ligand that blocks VLA-4 binding to vascular cell adhesion molecule 1 (VCAM-1). 11,16,24 Compounds D and E ( Fig. 2D and 2E) are two novel VLA-4 ligands discovered in a high-throughput screen at the University of New Mexico Center for Molecular Discovery (http://pubchem.ncbi.nlm.nih.gov, AID: 529, 702).…”

A Small Molecule α4β1/α4β7Antagonist Differentiates between the Low-Affinity States of α4β1and α4β7: Characterization of Divalent Cation Dependence

“…TR14035 (Fig. 1) has been reported to potently inhibit both ␣ 4 ␤ 1 and ␣ 4 ␤ 7 Sircar et al, 1999a,b;Egger et al, 2002), and this was confirmed (Table 1).…”

“…Compound 2, a recently described ␣ 4 ␤ 1 antagonist (Hagmann et al, 2001), and compound 3, a structurally related analog, inhibited binding to both ␣ 4 ␤ 1 and ␣ 4 ␤ 7 (Table 1). An inactive analog, compound 4 (Hagmann et al, 2001;Egger et al, 2002), did not inhibit binding when tested at concentrations up to 100 M, demonstrating the importance of specific structural features to the activities of compounds 1, 2, and 3 (Kopka et al, 2002; Table 1). TR14035 (Fig.…”

“…Small molecule antagonists of ␣ 4 ␤ 7 that mimic the LDT motif have been described that block the binding of ␣ 4 ␤ 7 -expressing cells to MAdCAM-Ig in the presence of Mn 2ϩ (Carson et al, 1997;Shroff et al, 1998;Martin et al, 1999;Harriman et al, 2000;Egger et al, 2002). Similarly, antagonists of ␣ 4 ␤ 1 have been reported to block binding of Mn 2ϩ -activated (Jackson et al, 1997;Vanderslice et al, 1997;Lin et al, 1998;Hagmann et al, 2001;Muller et al, 2001) and unactivated ␣ 4 ␤ 1 (Chen et al, 1999) to ligand in vitro.…”