Tying the Knot: In Silico Design of Foldable Lasso Peptides

Significance: Lasso peptides are a unique class of ribosomally synthesized and post-translationally modified natural products with diverse biological activities and potential for therapeutic applications. Although direct synthesis would facilitate therapeutic design, it has not yet been possible to fold these short sequences to their threaded architecture without the help of biosynthetic enzyme stabilization. Our work explores strategies to enhance the stability of the pre-lasso structure, the essential precursor to lasso peptide formation. We find that sequence design, incorporating non-canonical amino acid residues, and design-guided cross-linking can augment stability to increase the likelihood of lasso motif accessibility. This work presents several strategies for the continued design of foldable lasso peptides.