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Identification and X‐ray Co‐crystal Structure of a Small‐Molecule Activator of LFA‐1‐ICAM‐1 Binding |
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| Authors: | Dr Martin Hintersteiner Dr Jörg Kallen Mario Schmied Christine Graf Dr Thomas Jung Gemma Mudd Dr Steven Shave Dr Hubert Gstach Prof Manfred Auer |
| Institution: | 1. Bioseutica BV, Corso Elvezia 4, 6900 Lugano (Switzerland);2. Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel (Switzerland);3. Affiliation when work was performed: Novartis Institutes for BioMedical Research, Brunnerstrasse 59, 1235 Vienna (Austria);4. The University of Edinburgh, School of Biological Sciences (CSE) and School of Biomedical Sciences (CMVM), CH Waddington Building, 3.07, The King's Buildings, Mayfield Road, Edinburgh, EH9 3JD (UK);5. Institute of Medical Chemistry, Medical Univ. of Vienna, Waehringerstrasse 10, 1090 Vienna (Austria) |
| 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. |
| Keywords: | high‐throughput screening LFA‐1 OBOC libraries small‐molecule activators structural biology |