Professor Jerssica Swanson		Dr. Gabe da Hora		Professor Andrew Roberts

Lasso peptides are an awe-inspiring class of threaded cyclic peptide natural products that exhibit diverse biological activities. Their uniquely threaded structures are often more stable than their cyclic and acyclic peptide counterparts—presenting an opportunity for their development into peptide therapeutics. A team led by Prof. Swanson (@swansongroup_ut) and Prof. Roberts (@agr_chemistry) in the chemistry department (@utahchemistry) at the University of Utah (@uutah) developed computational tools to simulate and better understand abiotic lasso peptide folding. “Nature uses enzymes (lasso cyclases) to orchestrate the presumed peptide folding events prior to the cyclization event that locks the threaded tail in place. We want to achieve this chemically and hypothesize that the peptide sequence contains enough information alone to fold into a pre-lasso conformation. We connected with the Swanson team to uncover the aspects of peptide folding that are difficult to visualize experimentally,” says Dr. Roberts.

This collaborative research is spearheaded by Dr. Gabe da Hora (@gabe_dahora), a postdoctoral scholar in the Swanson group, who developed several creative computational tools that can be used to predict pre-lasso conformation probability and handedness (chirality). “This has been a fun challenge for computational methods,” Dr. Swanson explained, “opening the doors to using machine learning combined with human intuition to unravel the folding reaction coordinates that may be transformational in our ability to compare and predict folding propensities of non-native sequences.” The team is now advancing these tools to design unnatural peptides that may fold into pre-lassos more favorably. “This is an essential first step toward the chemical synthesis of class II lasso peptides—which could enable general access to lasso peptide therapeutics that are inaccessible by biosynthetic methods. [1]We can make the nonthreaded forms easily, [2]and now we have a better understanding on how the lasso thread might be accessed abiotically,” says Dr. Roberts. In January 2024, the team published this fascinating interdisciplinary research in the Journal of the American Chemical Society and artwork by Addison Cooper, Cooper Graphics showing ‘manipulated’ lasso peptide folding made it to the journal cover!

1. Lasso peptides: exploring the folding landscape of Nature’s smallest interlocked motifs da Hora, G. C. A.; Oh, M.; Mifflin, M. C.; Digal, L. D.; Roberts, A. G.; Swanson, J. S.* J. Am. Chem. Soc. 2024, online (January 2, 2024), https://doi.org/10.1021/jacs.3c10126

2. Nonthreaded isomers of sungsanpin and ulleungdin lasso peptides inhibit H1299 cancer cell migration

Digal, L. D.; Samson, S.; Stevens, M.; Ghorai, A.; Kim, H.; Mifflin, M. C.; Carney, K.; Williamson, D.; Um, S.; Nagy, G.; Oh, D.-C.; Mendoza, M. C.; Roberts, A. G.* ACS Chem. Biol. 2024,19, 81. https://doi.org/10.1021/acschembio.3c00525

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