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Development of nitroalkene-based inhibitors to target STING-dependent inflammation.
Chang, Fei; Gunderstofte, Camilla; Colussi, Nicole; Pitts, Mareena; Salvatore, Sonia R; Thielke, Anne L; Turell, Lucia; Alvarez, Beatriz; Goldbach-Mansky, Raphaela; Villacorta, Luis; Holm, Christian K; Schopfer, Francisco J; Hansen, Anne Louise.
Afiliación
  • Chang F; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • Gunderstofte C; Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark.
  • Colussi N; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • Pitts M; Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.
  • Salvatore SR; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • Thielke AL; Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark.
  • Turell L; Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
  • Alvarez B; Laboratorio de Enzimología, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, 11400, Uruguay; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, 11800, Uruguay.
  • Goldbach-Mansky R; Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20850, USA.
  • Villacorta L; Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA. Electronic address: lvillacortaperez@msm.edu.
  • Holm CK; Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. Electronic address: holm@biomed.au.dk.
  • Schopfer FJ; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Pittsburgh Heart, Lung, Blood, And Vascular Medicine Institute (VMI), Pittsburgh, PA, USA; Pittsburgh Liver Research Center (PLRC), Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medi
  • Hansen AL; Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark. Electronic address: annelouisehansen@biomed.au.dk.
Redox Biol ; 74: 103202, 2024 08.
Article en En | MEDLINE | ID: mdl-38865901
ABSTRACT
Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a ß-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alquenos / Inflamación / Proteínas de la Membrana / Nitrocompuestos Límite: Animals / Humans Idioma: En Revista: Redox Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alquenos / Inflamación / Proteínas de la Membrana / Nitrocompuestos Límite: Animals / Humans Idioma: En Revista: Redox Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos