Fluorescent Small Molecule Probe to Modulate and Explore α2β1 Integrin Function
Collagen binding integrins are an important family of cell surface receptors that mediate bidirectionally signals between the interior of the cell and the extracellular matrix. The protein-protein interactions between cells and collagen are necessary for many physiological functions, but also promote diseases. For example, the interaction of α2β1 integrin and collagen has been shown to have an important role in thrombus formation and cancer spread. The fact that the discovery of small molecules that can block such protein-protein interactions is highly challenging has significantly hindered the discovery of pharmaceutical agents to treat these diseases. Here, we present a rationally designe…
Novel α2β1 integrin inhibitors reveal that integrin binding to collagen under shear stress conditions does not require receptor preactivation.
The interaction between α2β1 integrin (GPIa/IIa, VLA-2) and vascular collagen is one of the initiating events in thrombus formation. Here, we describe two structurally similar sulfonamide derivatives, BTT-3033 and BTT-3034, and show that, under static conditions, they have an almost identical effect on α2-expressing CHO cell adhesion to collagen I, but only BTT-3033 blocks platelet attachment under flow (90 dynes/cm(2)). Differential scanning fluorimetry showed that both molecules bind to the α2I domain of the recombinant α2 subunit. To further study integrin binding mechanism(s) of the two sulfonamides, we created an α2 Y285F mutant containing a substitution near the metal ion-dependent ad…
Blockage of collagen binding to integrin α2β1: structure–activity relationship of protein–protein interaction inhibitors
The interaction between the α2β1 integrin and collagen plays a crucial role in the development of pathological conditions, such as thrombus formation and cancer cell metastasis. Accordingly, the α2β1 integrin is a promising target for the development of new drug molecules to treat these diseases. Here, we have designed, synthesized, and measured in vitro a set of novel drug-like compounds that block the protein–protein interactions between α2β1 integrin and collagen. The obtained structure–activity relationship reveals the key features that are required for successful inhibition of this integrin–collagen interaction.