Cryptic enzymatic assembly of peptides armed with β-lactone warheads.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
01 Jul 2024
01 Jul 2024
Historique:
received:
13
12
2023
accepted:
29
05
2024
medline:
2
7
2024
pubmed:
2
7
2024
entrez:
1
7
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38951647
doi: 10.1038/s41589-024-01657-7
pii: 10.1038/s41589-024-01657-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : RCUK | Engineering and Physical Sciences Research Council (EPSRC)
ID : EP/V048929/1
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/V016083/1
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/V008552/1
Organisme : European Commission (EC)
ID : EP/Y023714/1
Informations de copyright
© 2024. The Author(s).
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