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  • Review Article
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Therapeutic antagonists and conformational regulation of integrin function

Nature Reviews Drug Discovery volume 2, pages 703–716 (2003)Cite this article

Key Points

  • Members of the integrin family of adhesion molecules are non-covalently-associated α/β heterodimers that mediate cell–cell, cell–extracellular matrix and cell–pathogen interactions by binding to distinct, but often overlapping, combinations of ligands.

  • Dysregulation of integrins is involved in the pathogenesis of many disease states, from autoimmunity and thrombotic vascular diseases to cancer metastasis, and so extensive efforts have been directed towards the discovery and development of integrin antagonists for clinical applications. Integrin antagonists are already well established as therapeutics for cardiovascular disease, and applications in other therapuetic areas, including inflammatory disease, seem extremely promising.

  • Integrin ligand-binding function is tightly linked to molecular conformation. On activation, dramatic rearrangements occur in the overall spatial relationships of integrin domains. Understanding the structural basis of integrin activation in detail is essential for understanding the mechanism of antagonism by therapeutics, as well as for the design of second-generation antagonists with novel mechanisms of action.

  • This review discusses examples of the three different classes of integrin antagonists discovered so far: α/β I-like competitive antagonists, α/β I-like allosteric antagonists and α I allosteric antagonists. These examples were chosen because they illustrate particularly well the mutually beneficial relationship between integrin drug discovery and our understanding of integrin structure and function.

Abstract

Integrins are a structurally elaborate family of adhesion molecules that transmit signals bi-directionally across the plasma membrane by undergoing large-scale structural rearrangements. By regulating cell–cell and cell–matrix contacts, integrins participate in a wide range of biological processes, including development, tissue repair, angiogenesis, inflammation and haemostasis. From a therapeutic standpoint, integrins are probably the most important class of cell-adhesion receptors. Recent progress in the development of integrin antagonists has resulted in their clinical application and has shed new light on integrin biology. On the basis of their mechanism of action, small-molecule integrin antagonists fall into three different classes. Each of these classes affect the equilibria that relate integrin conformational states, but in different ways.

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Figure 1: Integrin heterodimer composition.
Figure 2: Integrin architecture.
Figure 3: Domain organization and global conformational changes of the extracellular portion of integrins.
Figure 4: Model of integrin αLβ2, which contains an I domain, bound to ICAM-1.
Figure 5: Stereo view of alternative conformations of the αM I domain.
Figure 6: Ribbon diagram of the αL I domain in complex with an α I allosteric antagonist95.
Figure 7: αIIbβ3 headpiece and critical residues for ligand binding.
Figure 8: Chemical structures of small-molecule integrin antagonists.
Figure 9: Mechanisms of inhibition and impact on integrin conformation of small-molecule antagonists.

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Acknowledgements

We would like to thank T. Xiao and W. Yang for modelling of the αIIbβ3 headpiece, and J. Takagi, T. Vorup-Jensen, B.-H. Luo, M. Kim, G. Weitz-Schmidt, T. A. Kelly and J. W. Tilley for critically reading this manuscript.

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Authors and Affiliations

  1. Department of Anesthesia and Pathology, The Center for Blood Research, Harvard Medical School, 200 Longwood, Boston, 02115, Massachussets, USA

    Motomu Shimaoka & Timothy A. Springer

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  1. Motomu Shimaoka
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DATABASES

LocusLink

α4 integrin

β4 integrin

αvβ3

αvβ5

αIIbβ3

MAdCAM-1

VCAM-1

von Willebrand factor

Online Mendelian Inheritance in Man

Crohn's disease

multiple sclerosis

FURTHER INFORMATION

Encyclopedia of Life Sciences

integrins: signalling and disease

integrin superfamily

Glossary

INTEGRIN-EGF DOMAIN

A module in cysteine-rich repeats in the integrin β-subunit stalk region adopts a nosecone-shaped variant of the epidermal growth factor (EGF) fold, termed an integrin-EGF (I-EGF) domain.

SDS–PAGE

(Sodium dodecyl sulphate– polyacrylamide gel electrophoresis). A method for resolving a protein into its subunits and determining their separate molecular weights.

THROMBOCYTOPAENIA

A disorder in which the number of platelets is abnormally low, and which is sometimes associated with abnormal bleeding.

IMMUNOLOGICAL SYNAPSE

T-cell recognition of an antigen presenting cell (APC), which is the initial and crucial process in the antigen-specific immune response, takes place at the nanometer-scale gap of the interface between the T cell and APC. This interface is a specialized cell–cell junction, at which crucial signals to initiate and maintain the immune response are transduced from APC to T cell or vice versa. The interface is called an immunological synapse after the neuronal synapse, a segregated gap through which information is transmitted in chemical form (neurotransmitter) from one neuron to another.

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Shimaoka, M., Springer, T. Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discov 2, 703–716 (2003). https://doi.org/10.1038/nrd1174

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