TW264481B - Surface loop structural analogues of fibroblast growth factors - Google Patents

Abstract

Structural analogues of fibroblast growth factors have at least one amino acid deletion, insertion or replacement in the ninth or tenth (beta)-strand or the sequence that corresponds to the surface loop that connects the ninth and tenth (beta)-strands of the factor such that the interaction of (beta)-strands nine and ten with adjacent strands is not significantly perturbed. Preferred analogues have the amino acid deletion, insertion or replacement in the surface loop that extends from the ninth (beta)-strand to the tenth (beta)-strand and have the overall secondary and tertiary structure of the original factor. In some embodiments, the analogues are prepared by replacing the surface loop sequence in the ninth or tenth (beta)-strand with another amino acid sequence such as a loop sequence from another structurally related fibroblast growth factor or an interleukin. In one embodiment, residues 118 to 122 of human fibroblast growth factor-2 are replaced with structural elements derived from bovine acidic fibroblast growth factor; in another, the residues are replaced with structural elements derived from human interleukin-1(beta). The analogues bind to fibroblast growth factor receptor with high affinity, yet exhibit functional antagonism in in vitro assays to the activity of native fibroblast growth factor. One embodiment binds with high affinity to growth factor receptor and heparin, yet exhibits antagonism in in vitro mitogenic assays but agonism in in vivo angiogenic assays.