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Updated: Jun 13, 2025

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Published on: September 28, 2022

Substrate interactions guide cyclase engineering and lasso peptide diversification.

Susanna E Barrett^1,2, Song Yin³, Peter Jordan⁴

¹Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA.

Nature Chemical Biology

|September 11, 2024

Summary

This summary is machine-generated.

Researchers modeled how lasso cyclases form unique lasso peptides. Engineering these enzymes enables production of novel variants targeting integrin αvβ8 for cancer therapy.

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Area of Science:

Biochemistry
Molecular Biology
Structural Biology

Background:

Lasso peptides are stable molecules with a unique rotaxane conformation.
The mechanism of ATP-dependent lasso cyclase in forming these peptides is poorly understood due to enzyme instability.
Understanding this process is key to harnessing lasso peptides for therapeutic applications.

Purpose of the Study:

To elucidate the mechanism by which lasso cyclases constrain substrate peptides into lasso peptide products.
To engineer lasso cyclases for novel substrate acceptance and therapeutic applications.

Main Methods:

Combined substrate tolerance data, structural predictions, and bioinformatic analysis.
Utilized molecular dynamics simulations and mutational scanning to model enzyme-substrate interactions.
Rationally engineered diverse lasso cyclases to alter substrate specificity.

Main Results:

Developed a model for substrate peptide orientation within the lasso cyclase active site.
Successfully engineered multiple lasso cyclases to accept previously rejected substrates.
Demonstrated robust production of novel lasso peptide variants with high affinity for integrin αvβ8.

Conclusions:

The study provides a mechanistic model for lasso cyclase activity.
Enzyme engineering successfully expanded substrate specificity and created novel therapeutic candidates.
Engineered lasso cyclases offer a promising platform for developing anti-cancer agents targeting integrin αvβ8.