ArticleAngewandte Chemie (International ed. in English)2021
Chemical Evolution of Antivirals Against Enterovirus D68 through Protein-Templated Knoevenagel Reactions.
Article in Angewandte Chemie (International ed. in English), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 16 citations in OpenAlex.
- Click Reactions in Kinetic Target-Guided Synthesis: Progress in the Discovery of Inhibitors for Biological Targets.Methods and protocols · 2026Review
- Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins.Nature communications · 2024Article
- Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary.Molecules (Basel, Switzerland) · 2022Review
- Chemical Evolution of Antivirals Against Enterovirus D68 through Protein-Templated Knoevenagel Reactions.Angewandte Chemie (International ed. in English) · 2021Article
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Authors and funding
11 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
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