Cryptic Enzymatic Assembly of Peptides Armed with β-lactone Warheads

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2024 Jul 1

PMID 38951647

Authors

Guangcai Xu

Daniele Torri

Sebastian Cuesta-Hoyos

Deepanjan Panda

Luke R L Yates

Remi Zallot

Kehan Bian

Dongxu Jia

Andreea I Iorgu

Colin Levy

Sarah A Shepherd

Jason Micklefield

Affiliations

Soon will be listed here.

Abstract

Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin antibiotics. Peptides armed with electrophilic warheads have proven to be particularly effective covalent inhibitors, providing essential antimicrobial, antiviral and anticancer agents. Here we provide a full characterization of the pathways that nature deploys to assemble peptides with β-lactone warheads, which are potent proteasome inhibitors with promising anticancer activity. Warhead assembly involves a three-step cryptic methylation sequence, which is likely required to reduce unfavorable electrostatic interactions during the sterically demanding β-lactonization. Amide-bond synthetase and adenosine triphosphate (ATP)-grasp enzymes couple amino acids to the β-lactone warhead, generating the bioactive peptide products. After reconstituting the entire pathway to β-lactone peptides in vitro, we go on to deliver a diverse range of analogs through enzymatic cascade reactions. Our approach is more efficient and cleaner than the synthetic methods currently used to produce clinically important warhead-containing peptides.

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