Chemical Evolution of Antivirals Against Enterovirus D68 through Protein-Templated Knoevenagel Reactions.
aldol condensations
antivirals
chemical evolution
protease inhibition
protein-templated reactions
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
07 06 2021
07 06 2021
Historique:
received:
09
02
2021
pubmed:
23
3
2021
medline:
7
9
2021
entrez:
22
3
2021
Statut:
ppublish
Résumé
The generation of bioactive molecules from inactive precursors is a crucial step in the chemical evolution of life, however, mechanistic insights into this aspect of abiogenesis are scarce. Here, we investigate the protein-catalyzed formation of antivirals by the 3C-protease of enterovirus D68. The enzyme induces aldol condensations yielding inhibitors with antiviral activity in cells. Kinetic and thermodynamic analyses reveal that the bioactivity emerges from a dynamic reaction system including inhibitor formation, alkylation of the protein target by the inhibitors, and competitive addition of non-protein nucleophiles to the inhibitors. The most active antivirals are slowly reversible inhibitors with elongated target residence times. The study reveals first examples for the chemical evolution of bio-actives through protein-catalyzed, non-enzymatic C-C couplings. The discovered mechanism works under physiological conditions and might constitute a native process of drug development.
Identifiants
pubmed: 33749121
doi: 10.1002/anie.202102074
pmc: PMC8252737
doi:
Substances chimiques
Antiviral Agents
0
Carbon
7440-44-0
3C Viral Proteases
EC 3.4.22.28
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13294-13301Informations de copyright
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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