Development of nitroalkene-based inhibitors to target STING-dependent inflammation
Fei Chang,
Camilla Gunderstofte,
Nicole Colussi,
Mareena Pitts,
Sonia R. Salvatore,
Anne L. Thielke,
Lucia Turell,
Beatriz Alvarez,
Raphaela Goldbach-Mansky,
Luis Villacorta,
Christian K. Holm,
Francisco J. Schopfer,
Anne Louise Hansen
Affiliations
Fei Chang
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Camilla Gunderstofte
Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark
Nicole Colussi
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Mareena Pitts
Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA
Sonia R. Salvatore
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
Anne L. Thielke
Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark
Lucia Turell
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
Beatriz Alvarez
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
Raphaela Goldbach-Mansky
Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20850, USA
Luis Villacorta
Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA; Cooresponding author. Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310, USA
Christian K. Holm
Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark; Corresponding author. Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark
Francisco J. Schopfer
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 Medicine (C3M), Pittsburgh, PA, USA; Corresponding author. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Anne Louise Hansen
Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark; Corresponding author. Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark
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 β-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.
