The insulin-like growth factor 1 (IGF-1) pathway plays a crucial role in cancer cell proliferation. Thus, its inhibition represents a promising strategy for anti-cancer therapy. Due to the similarity of the IGF-1 receptor and insulin receptor, it is extremely challenging to find an inhibitor selective for IGF-1 only.
The international and interdisciplinary team led by Emrah Altindis from Boston College Biology Department and by Jiří Jiráček from IOCB Prague used bioinformatics to newly identify five viruses containing genes encoding viral insulin or IGF-1-like peptides (VILPs) closely resembling human insulin and IGF-1.
The scientists chose two viruses, Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-Sa (LCDV-Sa) and chemically synthesized their single and double-chain VILPs. The chemical synthesis of viral hormones was highly challenging because they are small proteins with the single-chain forms containing 62-64 amino acids and containing 3 disulfide bridges. The in vitro experiments showed that all the VILPs behaved similarly to insulin/IGF-1 and could bind to human insulin receptors and IGF-1 receptors which are involved in growth and metabolic pathways. Surprisingly, the single-chain MFRV inhibited only the growth pathway by binding to the IGF-1 receptor, while leaving the metabolic one untouched. In addition, prolonged cell exposure to MFRV-VILP led to a significant decrease in IGF-1 receptor gene expression.
This study introduced novel members of the insulin/IGF superfamily, characterized their binding mode by cryoEM, and identified viral hormonal inhibitors of the IGF-1 receptor. The results offer valuable insight into IGF-1 receptor action and inhibition and suggest possibilities for the development of therapeutic IGF-1R antagonists.
Read the paper: Chrudinová, M.; Kirk, N. S.; Chuard, A.; Venugopal, H.; Zhang, F.; Lubos, M.; Gelfanov, V.; Páníková, T.; Žáková, L.; Cutone, J.; Mojares, M.; DiMarchi, R.; Jiráček, J.; Altindis, E. A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression. Mol. Metab. 80, 2024, 101863. https://doi.org/10.1016/j.molmet.2023.101863
