Stereochemical inversion as a route to improved biophysical properties of therapeutic peptides exemplified by glucagon

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.