LAUSR

Peptides and small proteins are attractive therapeutic candidates due to their inherent selectivity and limited off-target effects. Unfortunately, their potential is often hindered by unfavorable physicochemical properties. This is particularly true in the case of glucagon, a peptide indispensable in the treatment of life-threatening hypoglycemia. Glucagon displays extremely low solubility in physiological buffers and suffers chemical degradation when the pH is adjusted in either direction. Here we systematically examine site-specific stereochemical inversion as a means to enhance aqueous solubility and stability, yet not diminish bio-potency or pharmacodynamics. We report several analogs that maintain full biological activity with substantially increased aqueous solubility, and resistance to fibrillation. We conclude that d-amino acids offer an attractive option for biophysical optimization of therapeutic peptides.Glucagon is a key therapeutic for hypoglycemia but its application is limited by low aqueous solubility. Here, the absolute configuration each residue of glucagon is systematically inverted, yielding several biologically active analogues with therapeutically relevant solubility arising from epimerisation at a single position.