CHEMICAL APPROACHES TO STUDYING AND MODULATING LANTHIPEPTIDE BIOSYNTHESIS
Yang, Yi
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https://hdl.handle.net/2142/133269
Description
Title
CHEMICAL APPROACHES TO STUDYING AND MODULATING LANTHIPEPTIDE BIOSYNTHESIS
Author(s)
Yang, Yi
Issue Date
2026-05-15
Director of Research (if dissertation) or Advisor (if thesis)
Ribosomally synthesized and post-translationally modified natural products produced by members of the human gut microbiome influence human health in a drastic but poorly understood manner. An important example of this is the enterococcal cytolysin which is directly responsible for an invariantly fatal form of hepatitis in patients with alcohol use disorder. One of the central goals of this thesis was to facilitate the discovery of small-molecule inhibitors of cytolysin biosynthesis through assay development. Cytolysin is activated by a protease called CylA. To quantify inhibitor activity, a FRET assay was developed to monitor proteolytic cleavage. This assay was used to evaluate a panel of α-amino boronic acid peptides which led to the discovery of inhibitors of cytolysin biosynthesis with nanomolar activity. Structure–activity relationship analysis showed that the presence of the boronic acid functionality and specific side-chain interactions, particularly involving an aspartate residue, were critical for maintaining inhibitory potency. Computational docking supported these observations by identifying key binding interactions within the enzyme active site.
Dehydropeptides are important intermediates in the biosynthesis of many natural products and serve as key points of divergence for the chemical mutagenesis of proteins; however, their synthesis remains challenging. A chemical method was developed to convert peptides containing residues with β-thiols into dehydropeptides. The optimized method was fully aqueous and used cyanamide to facilitate desulfurization at near-neutral pH under ambient conditions. Substrate scope studies demonstrated compatibility with a range of peptide sequences and functional groups, and mechanistic observations suggested that the transformation proceeds through formation of an isothiourea intermediate followed by syn-elimination. The method provides a practical and operationally simple strategy for generating dehydropeptides in biologically relevant environments.
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