A Non-Perturbative Molecular Grafting Strategy for Stable and Potent Therapeutic Peptide Ligands

Abstract

The gut-derived incretin hormone, glucagon-like peptide-1 (GLP1), plays an important physiological role in attenuating post-prandial blood glucose excursions in part by amplifying pancreatic insulin secretion. Native GLP1 is rapidly degraded by the serine protease, dipeptidyl peptidase-4 (DPP4); however, enzyme-resistant analogues of this 30-amino-acid peptide provide an effective therapy for type 2 diabetes (T2D) and can curb obesity via complementary functions in the brain. In addition to its medical relevance, the incretin system provides a fertile arena for exploring how to better separate agonist function at cognate receptors versus susceptibility of peptides to DPP4-induced degradation. We have discovered that novel chemical decorations can make GLP1 and its analogues completely DPP4 resistant while fully preserving GLP1 receptor activity. This strategy is also applicable to other therapeutic ligands, namely, glucose-dependent insulinotropic polypeptide (GIP), glucagon, and glucagon-like peptide-2 (GLP2), targeting the secretin family of receptors. The versatility of the approach offers hundreds of active compounds based on any template that target these receptors. These observations should allow for rapid optimization of pharmacological properties and because the appendages are in a position crucial to receptor stimulation, they proffer the possibility of conferring “biased” signaling and in turn minimizing side effects.

Two-Chamber Aminocarbonylation of Aryl Bromides and Triflates Using Amino Acids as Nucleophiles

“…However, the use of peptides as drugs has long been riddled with problems in regards to low bioavailability, often forcing parenteral administration, as well as related low metabolic stability. Several ways to overcome these issues through chemical modifications of the peptides have been devised, such as PEGylation, N- and C-terminal functionalization, − cyclization, and D -amino acid insertion. , N -aroylation- or heteroaroylation of amino acid residues is a strategy that has been used in a number of medicinal chemistry projects aimed at the development of bioactive peptides, where this strategy can improve affinity, reduce metabolic degradation as well as capping of basic amino groups. ,,, …”

Fluorine-induced polarity increases inhibitory activity of BPTI towards chymotrypsin

“…Fluorination can influence steric properties, the local electrostatics of the peptides and proteins and their hydrophobicity, as well as facilitate interactions with other functional groups through hydrogen or halogen bonding. 8,9 These changes can result in varying overall properties such as the secondary structure propensity, 10 folding behavior 11 and proteolytic stability of peptides [12][13][14] and protein-protein interactions as for instance association kinetics. 15 Studies have shown that the degree of fluorination is crucial for all these properties of peptides and proteins.…”

Fluorine-induced polarity increases inhibitory activity of BPTI towards chymotrypsin

“…Fluorination can influence steric properties, the local electrostatics of the peptides and proteins and their hydrophobicity. These changes can result in varying overall properties such as the secondary structure propensity, 8 folding behavior 9 and proteolytic stability of peptides [10][11][12] and protein-protein interactions as for instance association kinetics. 13 Studies have shown that the degree of fluorination is crucial for all these properties of peptides and proteins.…”