Using sulfuramidimidoyl fluorides that undergo sulfur(VI) fluoride exchange for inverse drug discovery.
Journal
Nature chemistry
ISSN: 1755-4349
Titre abrégé: Nat Chem
Pays: England
ID NLM: 101499734
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
25
04
2019
accepted:
23
07
2020
pubmed:
2
9
2020
medline:
23
2
2021
entrez:
2
9
2020
Statut:
ppublish
Résumé
Drug candidates that form covalent linkages with their target proteins have been underexplored compared with the conventional counterparts that modulate biological function by reversibly binding to proteins, in part due to concerns about off-target reactivity. However, toxicity linked to off-target reactivity can be minimized by using latent electrophiles that only become activated towards covalent bond formation on binding a specific protein. Here we study sulfuramidimidoyl fluorides, a class of weak electrophiles that undergo sulfur(VI) fluoride exchange chemistry. We show that equilibrium binding of a sulfuramidimidoyl fluoride to a protein can allow nucleophilic attack by a specific amino acid side chain, which leads to conjugate formation. We incubated small molecules, each bearing a sulfuramidimidoyl fluoride electrophile, with human cell lysate, and the protein conjugates formed were identified by affinity chromatography-mass spectrometry. This inverse drug discovery approach identified a compound that covalently binds to and irreversibly inhibits the activity of poly(ADP-ribose) polymerase 1, an important anticancer target in living cells.
Identifiants
pubmed: 32868886
doi: 10.1038/s41557-020-0530-4
pii: 10.1038/s41557-020-0530-4
pmc: PMC7541551
mid: NIHMS1614419
doi:
Substances chimiques
Sulfhydryl Compounds
0
Sulfur
70FD1KFU70
Fluorides
Q80VPU408O
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
906-913Subventions
Organisme : NIEHS NIH HHS
ID : P42 ES004699
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK046335
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES002710
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK046335
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES030443
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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