The insulin/IGF-1 signaling axis regulates cell metabolism and growth, and its dysregulation is implicated in several diseases, including cancer. Elevated IGF-1 levels and IGF1R overexpression drive tumor proliferation, survival, and therapy resistance. While IGF1R is a promising oncology target, selective inhibition remains challenging due to structural homology with the insulin receptor (IR). Existing IGF1R inhibitors lack specificity and cause hyperglycemia by inhibiting IR signaling.
Our lab recently identified viral insulin/IGF1-like peptides (VILPs), a novel protein family encoded by Iridoviridae viruses, sharing ~30–50% identity with human insulin and IGF-1. Chemically synthesized VILPs bind both IR and IGF1R, with most acting as agonists. Remarkably, VILPs from Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-1 (LCDV1) function as natural IGF1R-selective antagonists, sparing the IR.
Preliminary studies using chimeric VILPs demonstrate that the LCDV1-VILP C-domain and a Gly8>Ser substitution in the B-domain convert IGF-1 into an IGF1R antagonist; reversing these changes abolishes antagonism. To further define structural features driving antagonism, we are engineering IGF-1/MFRV-VILP chimeras and mutating five conserved residues shared among antagonistic VILPs. Candidate peptides will be screened in IGF1R-overexpressing murine embryonic fibroblasts to assess effects on receptor autophosphorylation and Akt/Erk signaling. Promising hits will advance to recombinant production and detailed analysis of IGF1R versus IR selectivity.
This platform provides a rational path to designing next-generation IGF1R antagonists with minimal IR cross-reactivity, addressing a critical limitation of current therapies and offering a novel therapeutic avenue for IGF1R-driven diseases.
