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.
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D.J.C. is an Australian Research Council Australian Laureate (FL150100146). Work in our laboratory on peptide scaffolds is supported by grants from the Australian Research Council (DP150100443) and the National Health and Medical Research Council (APP1107403 and APP1060225).
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