S46: Reprogramming the Lasso Peptide Scaffold for Drug Design

Lasso peptides are unique ribosomally-synthesized natural products that are posttranslationally matured into a curious structure that resembles a slipknot or lasso.  The covalenty knotted structure of lasso peptides endows the molecules with hyperstability against thermal and chemical denaturation as well as resistance to most proteases.  Because of these properties, the lasso peptide scaffold is of interest from a drug design perspective.  In order to utilize lasso peptides as drugs, however, we must be able to reprogram the peptide with arbitrary sequences of our choosing.  In other words, we must determine the extent of sequence space that is permissive to the lasso fold.  We have tackled this problem using a directed evolution approach and have found that lasso peptides are highly reprogrammable at the amino acid level.  I will also describe our initial forays into designing therapeutically relevant lasso peptides and highlight potential applications for these molecules.