Small constrained peptides combine the stability of small molecule drugs with the selectivity and potency of antibody-based therapeutics. However, peptide-based therapeutics have largely remained underexplored due to the limited diversity of naturally occurring peptide scaffolds, and a lack of methods to design them rationally. New computational design and wet lab methods developed at the Institute for Protein Design have now opened the door to rational design of a whole new world of hyper-stable drug-like peptide structures.
In an article published in Nature this week, Baker lab / IPD scientists and their collaborators describe the development of computational methods for de novo design of constrained peptides with exceptional stabilities. They used these computational methods to design 18-47 residue constrained peptides with diverse shapes and sizes. The designed peptides presented in the paper cover three broad categories:
1) genetically encodable disulfide cross-linked peptides,
2) synthetic disulfide cross-linked peptides with non-canonical sequences, and
3) cyclic peptides with non-canonical backbones and sequences.
Experimentally determined structures for these peptides are nearly identical to their design models.
By including D-amino acids (mirror images of the L-amino acids), and thus expanding the palette of building blocks, Baker lab scientists designed peptides in a sequence and structure space sampled rarely by Nature. Indeed, the article describes successful design of a cyclic 2-helix peptide of mix chirality that represents a shape beyond natural secondary- and tertiary structure.
These designed peptides also exhibit exceptional stability to thermal and chemical denaturation, and thus could serve as attractive scaffolds for design of novel peptide-based therapeutics. More broadly, development of this new computational toolkit to precisely design constrained peptides opens the door for “on-demand” development of a new generation of peptide-based therapeutics. See In the Pipeline.
These and other breakthroughs in computational protein design are also covered in a Nature review article by David Baker, Po-Ssu Huang, and Scott E. Boyken entitled “The coming of age of de novo protein design”, part of special supplement on The Protein World.
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The National Institutes of Health provided partial support for this work through grants P50 AG005136, T32-H600035., GM094597, GM090205, and HHSN272201200025C. Additional funding was provided by The Three Dreamers.