Discovering covalent inhibitors of protein-protein interactions from trillions of sulfur(VI) fluoride exchange-modified oligonucleotides.
Journal
Nature chemistry
ISSN: 1755-4349
Titre abrégé: Nat Chem
Pays: England
ID NLM: 101499734
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
received:
04
06
2022
accepted:
24
07
2023
medline:
6
12
2023
pubmed:
1
9
2023
entrez:
31
8
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37653229
doi: 10.1038/s41557-023-01304-z
pii: 10.1038/s41557-023-01304-z
doi:
Substances chimiques
Fluorides
Q80VPU408O
spike protein, SARS-CoV-2
0
Sulfur
70FD1KFU70
Spike Glycoprotein, Coronavirus
0
Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1705-1714Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 22074076, 21621003
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 51973112, 52225302
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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