ArticleNature chemistry2023
Discovering covalent inhibitors of protein-protein interactions from trillions of sulfur(VI) fluoride exchange-modified oligonucleotides.
Article in Nature chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Nucleic acid aptamers: new methods for selection, target validation, molecular diagnostics and therapeutics.Signal transduction and targeted therapy · 2026Review
- Sulfur(VI) Fluoride Exchange Chemistry in Polymer Functionalization: Post-Polymerization Modification, Interface Engineering, and Biopolymer Conjugation.Molecules (Basel, Switzerland) · 2026Review
- SuFEx chemistry for nucleosides, nucleotides, and nucleic acids.RSC chemical biology · 2026Review
- A decision-driven framework for the mass spectrometry analysis of previously uncharacterized protein modifications.STAR protocols · 2026Review
- Small-molecule degraders for oncogenic KRASNature communications · 2026Article
- Structural basis of DNA aptamer A58 targeting the N-terminal domain of sarbecoviruses nucleocapsid protein.The Journal of biological chemistry · 2026Article
- A DNA nanoflowers-based microneedle patch for transdermal gene and photodynamic therapy against melanoma.Journal of nanobiotechnology · 2026Article
- Advances in DNAzyme Selection, Molecular Engineering and Biomedical Applications.International journal of molecular sciences · 2026Review
- Covalent aptamers: agents with promising therapeutic and diagnostic potential.RSC chemical biology · 2026Review
- The Current Toolbox for Covalent Inhibitors: From Hit Identification to Drug Discovery.JACS Au · 2025Review
- Advances in sulfonyl exchange chemical biology: expanding druggable target space.Chemical science · 2025Review
- Diversity Oriented Clicking for Modular Synthesis.Nature reviews. Methods primers · 2025Article
- Selection of antibody-binding covalent aptamers.Communications chemistry · 2024Article
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Molecules that covalently engage target proteins are widely used as activity-based probes and covalent drugs. The performance of these covalent inhibitors is, however, often compromised by the paradox of efficacy and risk, which demands a balance between reactivity and selectivity. The challenge is more evident when targeting protein-protein interactions owing to their low ligandability and undefined reactivity. Here we report sulfur(VI) fluoride exchange (SuFEx) in vitro selection, a general platform for high-throughput discovery of covalent inhibitors from trillions of SuFEx-modified oligonucleotides. With SuFEx in vitro selection, we identified covalent inhibitors that cross-link distinct residues of the SARS-CoV-2 spike protein at its protein-protein interaction interface with the human angiotensin-converting enzyme 2. A separate suite of covalent inhibitors was isolated for the human complement C5 protein. In both cases, we observed a clear disconnection between binding affinity and cross-linking reactivity, indicating that direct search for the aimed reactivity-as enabled by SuFEx in vitro selection-is vital for discovering covalent inhibitors of high selectivity and potency.
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Registered trials
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