Identification and X-ray Co-crystal Structure of a Small-Molecule Activator of LFA-1-ICAM-1 Binding

被引：14

作者：

Hintersteiner, Martin ^{[3
]}

Kallen, Joerg ^{[6
]}

Schmied, Mario ^{[5
]}

Graf, Christine ^{[5
]}

Jung, Thomas ^{[5
]}

Mudd, Gemma ^{[1
,2
]}

Shave, Steven ^{[1
,2
]}

Gstach, Hubert ^{[4
]}

Auer, Manfred ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Sch Biol Sci CSE, Edinburgh EH9 3JD, Midlothian, Scotland

[2] CH Waddington, Sch Biomed Sci CMVM, Edinburgh EH9 3JD, Midlothian, Scotland

[3] Bioseutica BV, CH-6900 Lugano, Switzerland

[4] Med Univ Vienna, Inst Med Chem, A-1090 Vienna, Austria

[5] Novartis Inst BioMed Res, A-1235 Vienna, Austria

[6] Novartis Inst BioMed Res, CH-4056 Basel, Switzerland

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2014年 / 53卷 / 17期

基金：

英国生物技术与生命科学研究理事会;

关键词：

high-throughput screening; LFA-1; OBOC libraries; small-molecule activators; structural biology; FUNCTION-ASSOCIATED ANTIGEN-1; ONE-COMPOUND LIBRARIES; I-DOMAIN; THROMBOPOIETIN RECEPTOR; CONFORMATIONAL-CHANGES; LFA-1; INHIBITION; CELL ADHESION; INTEGRIN; AGONIST; LYMPHOCYTES;

D O I：

10.1002/anie.201310240

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

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.

引用

页码：4322 / 4326

页数：5

共 33 条

[1]

A Semisynthetic Fusicoccane Stabilizes a Protein-Protein Interaction and Enhances the Expression of K+ Channels at the Cell Surface [J].

Anders, Carolin ;

Higuchi, Yusuke ;

Koschinsky, Kristin ;

Bartel, Maria ;

Schumacher, Benjamin ;

Thiel, Philipp ;

Nitta, Hajime ;

Preisig-Mueller, Regina ;

Schlichthoerl, Guenter ;

Renigunta, Vijay ;

Ohkanda, Junko ;

Daut, Juergen ;

Kato, Nobuo ;

Ottmann, Christian .

CHEMISTRY & BIOLOGY, 2013, 20 (04) :583-593

[2]

Anderson M. E., PEPTIDES

[3]

[Anonymous], 2012, ANGEW CHEM INT EDIT, V51, P478

[4]

LFA-1-specific therapy prolongs allograft survival in rhesus macaques [J].

Badell, Idelberto R. ;

Russell, Maria C. ;

Thompson, Peter W. ;

Turner, Alexandra P. ;

Weaver, Tim A. ;

Robertson, Jennifer M. ;

Avila, Jose G. ;

Cano, Jose A. ;

Johnson, Brandi E. ;

Song, Mingqing ;

Leopardi, Frank V. ;

Swygert, Sarah ;

Strobert, Elizabeth A. ;

Ford, Mandy L. ;

Kirk, Allan D. ;

Larsen, Christian P. .

JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (12) :4520-4531

[5]

Cytokine receptor dimerization and activation: Prospects for small molecule agonists [J].

Boger, DL ;

Goldberg, J .

BIOORGANIC & MEDICINAL CHEMISTRY, 2001, 9 (03) :557-562

[6]

LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation [J].

Carrasco, YR ;

Fleire, SJ ;

Cameron, T ;

Dustin, ML ;

Batista, FD .

IMMUNITY, 2004, 20 (05) :589-599

[7]

Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine [J].

Cwirla, SE ;

Balasubramanian, P ;

Duffin, DJ ;

Wagstrom, CR ;

Gates, CM ;

Singer, SC ;

Davis, AM ;

Tansik, RL ;

Mattheakis, LC ;

Boytos, CM ;

Schatz, PJ ;

Baccanari, DP ;

Wrighton, NC ;

Barrett, RW ;

Dower, WJ .

SCIENCE, 1997, 276 (5319) :1696-1699

[8]

Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist [J].

Erickson-Miller, CL ;

DeLorme, E ;

Tian, SS ;

Hopson, CB ;

Stark, K ;

Giampa, L ;

Valoret, EI ;

Duffy, KJ ;

Luengo, JL ;

Rosen, J ;

Miller, SG ;

Dillon, SB ;

Lamb, P .

EXPERIMENTAL HEMATOLOGY, 2005, 33 (01) :85-93

[9]

The integrin LFA-1 signals through ZAP-70 to regulate expression of high-affinity LFA-1 on T lymphocytes [J].

Evans, Rachel ;

Lellouch, Annemarie C. ;

Svensson, Lena ;

McDowall, Alison ;

Hogg, Nancy .

BLOOD, 2011, 117 (12) :3331-3342

[10]

Hintersteiner Martin, 2012, J Chem Biol, V5, P63, DOI 10.1007/s12154-011-0071-9

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