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New insulin-like growth factor 1 (IGF-1) analogs for receptor studies and therapeutic applications
Lin, Jingjing ; Jiráček, Jiří (advisor) ; Hodek, Petr (referee) ; Lapčík, Oldřich (referee)
The insulin/IGF system is an evolutionary conserved network that includes three closely related peptide hormones (insulin, IGF-1 and IGF-2), three homologous tyrosine kinase receptors (IR-A, IR-B and IGF-1R), a distinct IGF-2 receptor (IGF-2R), and six IGF-binding proteins. While insulin signals mainly via IR, playing a key role in glucose homeostasis, IGFs mainly signal via IGF-1R to mediate normal human growth. A tight control of ligands and receptors expression is crucial for the proper functioning of the organism. Aberrant signaling by these receptors is manifested in many pathological conditions, including cancer, growth disorders, neurodegenerative diseases and diabetes. Hence, the insulin/IGF axis represents a promising therapeutic target. In view of the multiple unsuccessful clinical anticancer trials performed either with tyrosine kinase inhibitors or antibodies targeted against IGF-1R, the development of novel selective and receptor-specific insulin and IGF analogs with minimized side effects would be of interest. Our study began with the recombinant preparation of IGF-1 dimers in which IGF-1 monomers are interlinked between their C- and N-termini with Ser-Gly linkers (length of 8, 15 or 25 residues). The goal was to investigate whether the binding of two covalently linked IGF-1 molecules...
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