In atherosclerosis, damage to arteries leads to an increased likelihood of thrombosis and subsequent arterial blockage. Activation of platelet integrins by the cytoplasmic protein talin is a key step in this thrombosis formation. Structures of talin bound to the β3-integrin tail have revealed the precise molecular details of the binding interface, and the mechanism of activation, providing the opportunity to design specific inhibitors of integrin activation. Studies in mice suggest that prevention of this interaction may produce a beneficial anti-thrombotic effect without the pathological bleeding that commonly accompanies current anti-integrin therapeutics. 

Talin’s integrin binding site is shallow, making it impractical to inhibit the interaction via small molecules. As an alternative strategy, the structure of the bound β3-integrin will be used as a basis for modified small peptide inhibitors. Covalent side-chain linkages have been introduced into these peptides in an attempt to stabilise the secondary structure, improve binding affinity, aid cell penetration and prevent degradation by proteases. CD and NMR spectroscopy studies have been used to characterise the peptidomimetic structure and talin binding affinity. In addition, the ability of these peptides to enter human and animal cells has also been investigated. The results provide insights into the effects of covalent linkages on peptide structure and activity, and paves the way for integrin inhibition testing and the development of a novel class of anti-thrombotic agent.