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

Marchetti, Carlo; Swartzwelter, Benjamin J; Gamboni, Fabia; Neff, C. Preston; Richter, Katrin; Azam, Tania; Carta, Sonia; Tengesdal, Isak W.; Nemkov, Travis; D’Alessandro, Angelo; Henry, Curtis J.; Jones, Gordon E.; Goodrich, Scott A.; Laurent, Joseph P. St.; Jones, Terry M.; Scribner, Curtis L.; Barrow, Robert B.; Altman, Roy D.; Skouras, Damaris B.; Gattorno, Marco; Grau, Veronika; Janciauskiene, Sabina; Rubartelli, Anna; Joosten, Leo A. B.; Dinarello, Charles A.

doi:10.1073/pnas.1716095115

Cited by 419 publications

(325 citation statements)

References 47 publications

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“…OLT1177 prevents NLRP3 inflammasome oligomerization by inhibiting the interactions of NLRP3‐ASC and NLRP3‐caspase‐1 . Moreover, OLT1177 was found to be safe for humans at a daily oral dose of 1000 mg for 8 days …”

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 98%

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Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 98%

“…132 Moreover, OLT1177 was found to be safe for humans at a daily oral dose of 1000 mg for 8 days. 133 MicroRNA-based inhibition of the NLRP3 inflammasome…”

Section: Small-molecule Inhibitors Of the Nlrp3 Inflammasomementioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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“…161 Oridonin decreased the ability of NLRP3 to interact with NEK7, a protein that may modulate its activation. 161 OLT1177 is a small non-lipophilic molecule that was found to inhibit the NLRP3 inflammasome 162 and demonstrated suppressed joint inflammation in murine models of acute arthritis. 163 How OLT1177 blocks NLRP3 engagement is still unclear; however, the preclinical studies in mice indicate that this molecule could be a promising compound to test in patients with joint disorders.…”

Section: Nlrp3 Inhibitorsmentioning

confidence: 99%

Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

125

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Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

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“…[13][14][15][16] Moreover, new drugs targeting components of the proinflammatory pathways that are responsible for the autoinflammatory phenotype are in development. They comprise small molecules that inhibit the NLRP3 inflammasome, including MCC950, 17 CY-09, 18 and OLT1177, 19 which is currently being evaluated in a phase 2 clinical study.…”

mentioning

confidence: 99%