Heterogeneous‐Backbone Foldamer Mimics of a Computationally Designed, Disulfide‐Rich Miniprotein. (27th November 2018)

• Record Type: Journal Article
• Authors: Cabalteja, Chino C.; Mihalko, Daniel S.; Horne, W. Seth
• Is Part Of: Chembiochem. Volume 20:Number 1(2019)
• Page Start: 103
• Page End: 110
• Publication Date: 2018-11-27
• Subjects: disulfide-rich peptides -- foldamers -- heterogeneous backbones -- protein design -- protein mimetics; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201800558
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Disulfide‐rich peptides have found widespread use in the development of bioactive agents; however, low proteolytic stability and the difficulty of exerting synthetic control over chain topology present barriers to their application in some systems. Herein, we report a method that enables the creation of artificial backbone ("foldamer") mimics of compact, disulfide‐rich tertiary folds. Systematic replacement of a subset of natural α‐residues with various artificial building blocks in the context of a computationally designed prototype sequence leads to "heterogeneous‐backbone" variants that undergo clean oxidative folding, adopt tertiary structures indistinguishable from that of the prototype, and enjoy proteolytic protection beyond that inherent to the topologically constrained scaffold. Collectively, these results demonstrate systematic backbone substitution to be a viable method to engineer the properties of disulfide‐rich sequences and expands the repertoire of protein mimicry by foldamers to an exciting new structural class. Abstract : Systematic alteration of peptide backbone chemical composition in a prototype sequence with a compact, disulfide‐rich folded architecture yields mimics with identical folds and enhanced resistance to degradation by proteases. The approach described constitutes a valuable new method to engineer properties in disulfide‐rich peptides and proteins.