Novel integrin antagonists derived from thrombospondins.
Specific antagonists have been successfully developed for several different integrins. Clinical trials have been initiated to study therapeutic uses of these inhibitors in cancer, thrombosis, and inflammatory diseases. Most efforts to date have focused on the platelet integrin alphaIIbbeta3, endothelial alphavbeta3, and the leukocyte integrin alpha4beta1. However, the integrin family contains additional members with interesting tissue specificities and functional properties that could also be useful molecular targets for disease intervention. In many cases, specific recognition motifs for these integrins have not been identified, which has precluded development of specific antagonists. Our recent studies of thrombospondin-1 and thrombospondin-2 recognition by integrins have revealed novel motifs for alpha3beta1 and alpha6beta1 integrins as well as new motifs recognized by the well studied alpha4beta1 integrin. These three integrins play distinct roles in angiogenesis and its modulation by thrombospondins. This review will discuss recent insights into the specificities of alpha3beta1 and alpha6beta1 integrins, their functions in angiogenesis, and potential applications for antagonists of these integrins and of alpha4beta1 to control pathological angiogenesis and other diseases.
Calzada
Maria J
MJ
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Roberts
David D
DD
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018955:CD36 Antigens / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding; D019699:Thrombospondins / Q000737:chemistry* / Q000494:pharmacology* / Q000502:physiology
D020533:Angiogenesis Inhibitors; D018955:CD36 Antigens; D016023:Integrins; D019699:Thrombospondins