Richard DiMarchi of Indiana University - Bloomington and the Gill Center for Biomolecular Science will present a lecture entitled: Chemical Evoluation of Naturally Sourced Peptides to Novel Drugs.
Abstract: We have championed the chemical optimization of native hormones for chemical biology purposes, some of which eventually matured to valuable medicines. From the earliest demonstration with lispro-insulin to the most recent discovery of single molecule, mixed incretin agonists we have pursued macromolecules directed at the successful management of endocrine diseases. The integrated biology of these peptides, proteins and nuclear hormones has provided a library of drug candidates that have progressed to advanced clinical studies in metabolic diseases and obesity. Insulin therapy that is responsive to glucose concentration remains an elusive goal for our research.
In the pursuit of our objectives the emergence of high throughput diversity screening has provided an important tool in the search for novel receptor ligands. Nonetheless, natural sources still constitute an important cradle of molecular diversity that exceed the practical limit in synthetic libraries. We recently identified such a family of viral insulin-like peptides (VILPs). We report here that one of these VILPs, Lymphocystis disease virus-1(LCDV1)-VILP, has the unique property of being a potent, full, and selective antagonist of the insulin-like growth factor 1 receptor (IGF-1R).
Through an optimized chemical synthesis of these VILPs and related analogs in which human insulin/IGF-1 chains were substituted for VILP chains, we demonstrate the coordinated importance of the B- and C-chains of the VILP in regulating this activity. Concurrently we demonstrate that the 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 insulin receptor family and identify a set of antagonists of potential medicinal importance..