Identification and X-ray Co-crystal structure of a small-molecule activator of LFA-1-ICAM-1 binding

Abstract

Stabilization of protein-protein interactions by small molecules is a concept with few examples reported to date. Herein we describe the identification and X-ray co-crystal structure determination of IBE-667, an ICAM-1 binding enhancer for LFA-1. IBE-667 was designed based on the SAR information obtained from an on-bead screen of tagged one-bead one-compound combinatorial libraries by confocal nanoscanning and bead picking (CONA). Cellular assays demonstrate the activity of IBE-667 in promoting the binding of LFA-1 on activated immune cells to ICAM-1. Tuned up: The LFA-1 ICAM-1 interaction is a fundamental step in T-cell activation in response to antigen encounter. A small-molecule activator of LFA-1, IBE-667, was identified by confocal on-bead screening. The identified activator binds to LFA-1 I domain, as revealed by the co-crystal structure, and increases the affinity of LFA-1 for ICAM-1 on activated T-cells. © 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.