Integrins as drug targets: is there a future?

<p>In 1981 fibroblasts were found to adhere to a surface coated in fibronectin and by 1984 the amino acid sequence Arg-Gly-Asp-Ser (RGDS) was identified in a 30-mer fragment of fibronectin as the site essential for supporting adhesion. The RGD sequence was subsequently found to be a common motif with many proteins containing this sequence such as fibronectin, vitronectin and fibrinogen suggesting a family of RGD-containing proteins that were involved in cell adhesion (Humphries et al. 2006). </p> <p>The initial characterization of the RGD-dependent fibronectin receptor identified a 140kDa protein. AT the same time work on immune cell antigens showed that two antigens, LFA-1 (T-cells) and Mac-1 (macrophages) while expressed on different cells had similar structures. Both were composed of an a and b subunit. While both a-subunits were different both b- subunits were probably identical. The platelet fibronectin receptor was identified as a complex of glycoproteins (GP) IIb and IIIa. The vitronectin receptor was also found to have two subunits and while it bound RGD peptides it did not bind to fibronectin. Thus, there was a picture developing of a family of heterodimeric adhesion proteins that interact with RGDcontaining proteins. While all bound RGD there was evidence that some of the receptors were specific for certain RGD-containing proteins. It was also evident that leucocytes have a family of 3 a/b heterodimeric proteins that share a common b-subunit. Evidence that an anti-GPIIb/IIIa antibody also bound to leucocytes suggested that GPIIb/IIIa may be related to the leucocyte surface markers. This was confirmed in a study which showed that all of the a-subunits came from the same gene family. The cDNA for an 89 kDa subunit of a glycoprotein that mediates cell adhesion was isolated and characterised and this protein was called integrin. By 1987 it had become clear that these three different receptor families – leucocyte surface receptors, platelet GPIIb/IIIa (aIIbb3) and matrix adhesion receptors - were all related. They were grouped together into a super family of distinct but related receptors called Integrins (Hynes 1987). Some but not all of these receptors bound to a family RGD-containing proteins in an RGD-dependent manner. </p> <p>Initial evidence suggested that a-subunits only interacted with a single b-subunit (only 3 b- subunits were known) and that ligand specificity was conferred by the a-subunit. Thus, integrins were thought to consist of 3 families based around the unique b-subunits. However, there are currently 18 identified a-subunits and 8 b-subunits and it is clear that some a subunits, especially aV are capable of interacting with multiple b-subunits. Thus, integrins can be grouped into sub-families although the precise arrangement is complex (Cox et al. 2010). One approach to categorising integrins is to use a phylogenetic tree where integrin subunits can be grouped according to similarity in their gene sequences (HightWarburton and Parsons 2019). </p> <p>This discovery of integrins created great opportunity for drug discovery. Integrins were associated with many major diseases with unmet needs. Their presence on leucocytes suggested a role in autoimmune diseases. Their role as cell adhesion molecules suggested a potential role in cancer and their presence on platelets suggested a role in thrombosis and cardiovascular disease. Furthermore the RGD-dependent nature of the interactions provided a hit compound for a small molecule discovery programme and the discovery of inhibitory monoclonal antibodies provided the potential for a biotechnology solution. While monoclonal antibody technology had been around for over 10-years they had yet to be deployed clinically.</p>