Selectivity of the collagen-binding integrin inhibitors, TC-I-15 and obtustatin

Integrins are a family of 24 adhesion receptors which are both widely-expressed and important in many pathophysiological cellular processes, from embryonic development to cancer metastasis. Hence, integrin inhibitors are valuable research tools which may have promising therapeutic uses. Here, we focus on the four collagenbinding integrins alpha 1 beta 1, alpha 2 beta 1, alpha 10 beta 1 and alpha 11 beta 1. TC-I-15 is a small molecule inhibitor of alpha 2 beta 1 that inhibits platelet adhesion to collagen and thrombus deposition, and obtustatin is an alpha 1 beta 1-specific disintegrin that inhibits angiogenesis. Both inhibitors were applied in cellular adhesion studies, using synthetic collagen peptide coatings with selective affinity for the different collagen-binding integrins and testing the adhesion of C2C12 cells transfected with each. Obtustatin was found to be specific for alpha 1 beta 1, as described, whereas TC-I-15 is shown to be non-specific, since it inhibits both alpha 1 beta 1 and alpha 11 beta 1 as well as alpha 2 beta 1. TC-I-15 was 100-fold more potent against alpha 2 beta 1 binding to a lower-affinity collagen peptide, suggestive of a competitive mechanism. These results caution against the use of integrin inhibitors in a therapeutic or research setting without testing for cross-reactivity.

Automated summary

Integrins, a family of 24 adhesion receptors, play crucial roles in pathophysiological cellular processes. Integrin inhibitors show promising therapeutic uses but caution is needed due to potential cross-reactivity.