OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation

Carlo Marchetti, Benjamin Swartzwelter, Fabia Gamboni, Charles P Neff, Katrin Richter, Tania Azam, Sonia Carta, Isak Tengesdal, Travis Nemkov, Angelo D'Alessandro, Curtis Henry, Gerald S Jones, Scott A Goodrich, Joseph P St Laurent, Terry M Jones, Curtis L Scribner, Robert B Barrow, Roy D Altman, Damaris B Skouras, Marco GattornoVeronika Grau, Sabina Janciauskiene, Anna Rubartelli, Leo A B Joosten, Charles A Dinarello

Research output: Contribution to journalArticlepeer-review

Abstract

Activation of the NLRP3 inflammasome induces maturation of IL-1β and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active β-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1β and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1β levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1β release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1β release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1β precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1β content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.

Original languageEnglish
Pages (from-to)E1530-E1539
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number7
DOIs
Publication statusPublished - Feb 13 2018

Keywords

  • Animals
  • Anti-Inflammatory Agents/chemistry
  • Caspase 1/metabolism
  • Cells, Cultured
  • Humans
  • Inflammasomes/antagonists & inhibitors
  • Inflammation/chemically induced
  • Interleukin-18/metabolism
  • Interleukin-1beta/metabolism
  • Lipopolysaccharides/toxicity
  • Macrophages/drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein/genetics
  • Nitriles/chemistry

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