Mandarin Fish Ranavirus Viral Insulin/IGF-Like Peptide Inhibits Human IGF-1 Receptor

Our recent studies published in PNAS and Molecular Metabolism showed for the very first time that viruses possess genes encoding viral insulin/IGF-1 like peptides (VILPs). These two studies provided several important insights on VILPs: 1. Identified VILPs in six different Iridoviridae viruses 2. Showed that chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin-like) VILPs can bind to human insulin and IGF-1 receptors and stimulate downstream signaling. 3. Demonstrated that VILPs can increase glucose uptake in vitro and in vivo. 4. Identified the unique tissue-specific effects of VILPs. 5. Found sequences of these viruses in the human gut and plasma virome. In the present study, we focused on a novel, Mandarin Fish Ranavirus (MFRV) VILP and characterized both sc and dc forms for the first time. MFRV scVILP binds to human IGF1R with an affinity 100x higher than insulin, making it a VILP with the highest affinity to this receptor so far discovered. MFRV scVILP also activates IGF1R phosphorylation and post-receptor signaling. Interestingly, although MFRV scVILP is a weak agonist of IGF1R, it inhibits IGF-1 signaling at higher concentrations. When we treat cells with both IGF-1 and MFRV VILP, MFRV scVILP inhibits IGF-1 (10nM) stimulated IGF1R phosphorylation and activation of PI3K and MAPK pathways at high concentrations (> 250 nM). Surprisingly, the dc version of MFRV VILP neither bind nor stimulate IGF1R. This suggests that the C-chain of MFRV VILP is essential for both binding to IGF1R and the IGF-1 inhibitory effects. Taken together, our results revealed that MFRV scVILP is a novel antagonist/inhibitor of IGF-1R. IGF1R signaling is overly activated in breast, prostate and colorectal cancers. Despite tremendous efforts to develop an effective inhibitor of IGF1R, these attempts failed. MFRV VILP has the potential to contribute development of new therapeutics in cancer therapy and to help us better understand ligand-receptor interactions and mechanisms of IGF1R inhibition. Disclosure M. Chrudinova: None. V. Gelfanov: Employee; Self; Novo Nordisk, Employee; Spouse/Partner; Eli Lilly and Company. L. Zakova: None. J. Cutone: None. A. Powis: None. K. Sevgi: None. J. Jiracek: None. R. Dimarchi: Employee; Self; Novo Nordisk. E. Altindis: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (K01DK117967)