Linking molecular evolution to molecular grafting

Abstract

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Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions

“…The grafting of de novo identified peptides to improve their stability and bioavailability has been attempted on a variety of scaffolds [23][24][25][26] . These past studies revealed that successful grafting is highly dependent on the combination and compatibility between grafted peptides and scaffold proteins 25,26 .…”

“…The grafting of de novo identified peptides to improve their stability and bioavailability has been attempted on a variety of scaffolds [23][24][25][26] . These past studies revealed that successful grafting is highly dependent on the combination and compatibility between grafted peptides and scaffold proteins 25,26 . As such, the selection of scaffold protein is a key consideration, as it determines the success of peptide grafting while conferring desirable properties such as metabolic stability and cell permeability to the engineered products [24][25][26] .…”

“…These past studies revealed that successful grafting is highly dependent on the combination and compatibility between grafted peptides and scaffold proteins 25,26 . As such, the selection of scaffold protein is a key consideration, as it determines the success of peptide grafting while conferring desirable properties such as metabolic stability and cell permeability to the engineered products [24][25][26] . To cater for this broad spectrum of desirable features, disulfide-stabilized peptides and miniproteins have been engineered to act as specialized scaffolds for peptide grafting [23][24][25][26] .…”

“…As such, the selection of scaffold protein is a key consideration, as it determines the success of peptide grafting while conferring desirable properties such as metabolic stability and cell permeability to the engineered products [24][25][26] . To cater for this broad spectrum of desirable features, disulfide-stabilized peptides and miniproteins have been engineered to act as specialized scaffolds for peptide grafting [23][24][25][26] . However, these specialized scaffolds are small non-human proteins with no particular bioactivities of their own.…”

“…In general, macrocyclic peptides display greater affinities for targets than linear peptides due to their constrained cyclic structures. An intriguing possibility in extending the applicability of these macrocyclic peptides is to 'engraft' them onto protein scaffolds to allow for functional combinations of peptide and protein 18,[22][23][24][25][26] . However, grafting de novo identified peptides to protein loops has been challenging due to the potential misfolding of both the grafted peptide and the host protein 26 .…”