3 years ago

Synthetic Advances in Insulin-like Peptides Enable Novel Bioactivity

Synthetic Advances in Insulin-like Peptides Enable Novel Bioactivity
Richard DiMarchi, Pengyun Li, Fa Liu, John Mayer, Vasily Gelfanov
Insulin is a miraculous hormone that has served a seminal role in the treatment of insulin-dependent diabetes for nearly a century. Insulin resides within in a superfamily of structurally related peptides that are distinguished by three invariant disulfide bonds that anchor the three-dimensional conformation of the hormone. The additional family members include the insulin-like growth factors (IGF) and the relaxin-related set of peptides that includes the so-called insulin-like peptides. Advances in peptide chemistry and rDNA-based synthesis have enabled the preparation of multiple insulin analogues. The translation of these methods from insulin to related peptides has presented unique challenges that pertain to differing biophysical properties and unique amino acid compositions. This Account presents a historical context for the advances in the chemical synthesis of insulin and the related peptides, with division into two general categories where disulfide bond formation is facilitated by native conformational folding or alternatively orthogonal chemical reactivity. The inherent differences in biophysical properties of insulin-like peptides, and in particular within synthetic intermediates, have constituted a central limitation to achieving high yield synthesis of properly folded peptides. Various synthetic approaches have been advanced in the past decade to successfully address this challenge. The use of chemical ligation and metastable amide bond surrogates are two of the more important synthetic advances in the preparation of high quality synthetic precursors to high potency peptides. The discovery and application of biomimetic connecting peptides simplifies proper disulfide formation and the subsequent traceless removal by chemical methods dramatically simplifies the total synthesis of virtually any two-chain insulin-like peptide. We report the application of these higher synthetic yield methodologies to the preparation of insulin-like peptides in support of exploratory in vivo studies requiring a large quantity of peptide. Tangentially, we demonstrate the use of these methods to study the relative importance of the IGF-1 connecting peptide to its biological activity. We report the translation of these finding in search of an insulin analog that might be comparably enhanced by a suitable connecting peptide for interaction with the insulin receptor, as occurs with IGF-1 and its receptor. The results identify a unique receptor site in the IGF-1 receptor from which this enhancement derives. The selective substitution of this specific IGF-1 receptor sequence into the homologous site in the insulin receptor generated a chimeric receptor that was equally capable of signaling with insulin or IGF-1. This novel receptor proved to enhance the potency of lower affinity insulin ligands when they were supplemented with the IGF-1 connecting peptide that similarly enhanced IGF-1 activity at its receptor. The chimeric insulin receptor demonstrated no further enhancement of potency for native insulin when it was similarly prepared as a single-chain analogue with a native IGF-1 connecting peptide. These results suggest a more highly evolved insulin receptor structure where the requirement for an additional structural element to achieve high potency interaction as demonstrated for IGF-1 is no longer required.

Publisher URL: http://dx.doi.org/10.1021/acs.accounts.7b00227

DOI: 10.1021/acs.accounts.7b00227

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