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Using sulfuramidimidoyl fluorides that undergo sulfur(VI) fluoride exchange for inverse drug discovery.
Brighty, Gabriel J; Botham, Rachel C; Li, Suhua; Nelson, Luke; Mortenson, David E; Li, Gencheng; Morisseau, Christophe; Wang, Hua; Hammock, Bruce D; Sharpless, K Barry; Kelly, Jeffery W.
Afiliación
  • Brighty GJ; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Botham RC; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
  • Li S; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Nelson L; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
  • Mortenson DE; Codexis, Redwood City, CA, USA.
  • Li G; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Morisseau C; School of Chemistry, Sun Yat-Sen University, Guangzhou, P. R. China.
  • Wang H; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Hammock BD; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Sharpless KB; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
  • Kelly JW; Gilead Sciences Inc., Foster City, CA, USA.
Nat Chem ; 12(10): 906-913, 2020 10.
Article en En | MEDLINE | ID: mdl-32868886
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Sulfhidrilo / Azufre / Descubrimiento de Drogas / Fluoruros Límite: Humans Idioma: En Revista: Nat Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Sulfhidrilo / Azufre / Descubrimiento de Drogas / Fluoruros Límite: Humans Idioma: En Revista: Nat Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido