A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor

Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such a family of viral insulin-like peptides (VILPs). We sought to advance the chemical methods in synthesis to explore the structure-function relationship within these VILPs, and the molecular basis for differential biological activities relative to human IGF-1 and insulin. Optimized chemical methods in synthesis were established for a set of VILPs and related analogs. These modified forms included the substitution of select VILP chains with those derived from human insulin and IGF-1. Each peptide was assessed in vitro for agonism and antagonism at the human insulin and the human insulin-like growth factor 1 receptor (IGF-1R). We report here that one of these VILPs, lymphocystis disease virus-1 (LCDV1)-VILP, has the unique property to be a potent and full antagonist of the IGF-1R. We demonstrate the coordinated importance of the B- and C-chains of the VILP in regulating this activity. Moreover, mutation of the glycine following the first cysteine in the B-chain of IGF-1 to serine, in concert with substitution to the connecting peptide of LCDV1-VILP, converted native IGF-1 to a high potency antagonist. The results reveal novel aspects in ligand–receptor interactions at the IGF-1 receptor and identify a set of antagonists of potential medicinal importance. [Display omitted] •Improved chemical synthesis of single-chain and two-chain analogs of insulin-like peptides derived from viral sources.•Characterization of virus-1 (LCDV1)-VILP as a potent and selective IGF-1 antagonist.•Molecular identification of the amino acid changes in the B- and C-domains that define IGF-1 agonism versus antagonism.•Correlation of a (LCDV1)-VILP residue essential to IGF-1 receptor antagonism with a proinsulin mutation linked with diabetes.