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    Cryptic enzymatic assembly of peptides armed with β-lactone warheads

    Xu, G ORCID logoORCID: https://orcid.org/0000-0003-4074-5165, Torri, D ORCID logoORCID: https://orcid.org/0000-0003-1297-4235, Cuesta-Hoyos, S, Panda, D, Yates, LRL ORCID logoORCID: https://orcid.org/0000-0002-6432-8289, Zallot, R ORCID logoORCID: https://orcid.org/0000-0002-7317-1578, Bian, K, Jia, D, Iorgu, AI, Levy, C, Shepherd, SA ORCID logoORCID: https://orcid.org/0000-0002-7321-1234 and Micklefield, J ORCID logoORCID: https://orcid.org/0000-0001-8951-4873 (2024) Cryptic enzymatic assembly of peptides armed with β-lactone warheads. Nature Chemical Biology, 20 (10). pp. 1371-1379. ISSN 1552-4450

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    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. (Figure presented.)

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