Designing macrocyclic disulfide-rich peptides for biotechnological applications

Conan K. Wang, David J. Craik

Bioactive peptides have potential as drug leads, but turning them into drugs is a challenge because of their typically poor metabolic stability. Molecular grafting is one approach to stabilizing and constraining peptides and involves melding a bioactive peptide sequence onto a suitable molecular scaffold. This method has the benefit of improving the stability of the bioactive peptide lead and potentially expanding its functionality. Here we step through the molecular grafting process and describe its successes and limitations. So far, molecular grafting has been successfully used to improve the stability of peptide drug leads, to enhance conformational rigidity, to facilitate delivery to intracellular targets, and in some cases to increase efficacy in oral administration. Although applications of molecular grafting have focused mainly on therapeutic applications, including those for pain, metabolic disease, and cancer, its potential uses are much broader, and we hope this Perspective will inspire wider applications of this molecular design tool in biotechnology.