Delving into the Latest Updates on NLRP3 inflammasome inhibitor(Exscientia/University of Oxford) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

NLRP3

Action

inhibitors

Mechanism

NLRP3 inhibitors(NACHT, LRR and PYD domains-containing protein 3 inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Alzheimer Disease

Originator Organization

Exscientia AI Ltd.

Active Organization-

Inactive Organization

University of OxfordExscientia AI Ltd.

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Cardiovascular diseases remain the leading cause of disability and death in the Western world. Effective cardioprotection involves limiting ischemia/reperfusion injury (IRI), including cell death (pyroptosis) driven by the NLRP3 inflammasome. While various cardiac resident cellular populations contribute to cardioprotection, it remains unclear whether targeting resident macrophages is inherently cardioprotective. Given that INF150, an NLRP3 inhibitor, exhibits varying abilities to penetrate cardiomyocytes and macrophages, we sought to address this question.

METHODS:

We studied the cardioprotective potential of INF150, the potent metabolite of the NLRP3 inhibitor INF195, in isolated hearts or cells. In isolated hearts, we measured infarct size, caspase-1 cleavage, and interleukins (IL) release, while in macrophages, naïve H9c2 and differentiated H9c2 cells, we analyzed cell viability, and pyroptosis markers, including IL-1β release and Gasdermin D cleavage, following hypoxia/reoxygenation (H/R).

RESULTS AND CONCLUSION:

While INF150 effectively shielded macrophages from LPS/ATP challenges, it failed to penetrate H9c2 and differentiated H9c2, even at high concentrations (no changes in pyroptosis markers induced by H/R). In the isolated mice heart model, INF150 did not demonstrate cardioprotective effects: infarct size, IL-1β, cleaved caspase-1 levels did not change significantly across tested concentrations of INF150. These findings suggest that while INF150 shows promise in macrophage/phagocytic models, its inability to penetrate cardiomyocytes limits its effectiveness in the whole cardiac tissue. Our results underscore the importance of cardiomyocyte uptake for effective cardioprotection, highlighting the need for NLRP3 inhibitors capable of targeting these cells directly. Future research should focus on enhancing the delivery and cardiomyocyte uptake of NLRP3 inhibitors to achieve cardioprotection. Unlike its precursor, INF195, which penetrates H9c2 cells, INF150 does not appear to offer cardioprotection in the whole organ.

01 Apr 2025·INTERNATIONAL IMMUNOPHARMACOLOGY

Thiolutin, a novel NLRP3 inflammasome inhibitor, mitigates IgA nephropathy in mice

Article

Author: Che, Lishuang ; Zeng, Quanzuan ; Lin, Weiyuan ; Lin, Changda ; Li, Yuangen ; Shi, Shuhan ; Zhang, Yun

NLRP3 inflammasome plays a key role in IgA Nephropathy (IgAN) pathogenesis. Thiolutin (THL) is an NLRP3 inflammasome inhibitor with anti-inflammatory effects, but its role in IgAN is unclear. This study aimed to evaluate the protective efficacy of THL in IgAN mice, alongside assessing its inhibitory mechanisms. IgAN was induced by administration of bovine serum albumin combined with Staphylococcal Enterotoxin B in mice, followed by THL treatment. Kidney injury biomarkers, inflammatory cytokines, histological changes and the NLRP3 inflammasome pathway were assessed. The effect of THL on pyroptosis and action site on inflammasome was examined in J774A.1 cells, and co-immunoprecipitation was used to study specific protein interactions. In IgAN mice, THL treatment significantly reduced renal dysfunctional markers and histological injury without affecting hepatic function, accompanied by decreased serum IgA levels, renal IgA deposition and pro-inflammatory cytokine accumulation via regulating the mRNA and protein expression of key inflammasome components. It also attenuated pyroptosis and NLRP3 inflammasome activation instead of priming in macrophages, via disturbing the combination of NLRP3 with apoptosis-associated speck-like protein and NIMA-Related Kinase 7. THL has significant anti-inflammatory and renal protective effects in IgAN via inhibiting the NLRP3 inflammasome pathway. Its selective impact on the activation and assembly of the inflammasome, without affecting priming, highlights its potential as a targeted therapeutic agent in IgAN management.

01 Mar 2025·JOURNAL OF THROMBOSIS AND HAEMOSTASIS

Platelet-neutrophil aggregate formation induces NLRP3 inflammasome activation in vaccine-induced thrombotic thrombocytopenia

Article

Author: Cardoso, Sandra Wagner ; Sacramento, Carolina Q ; Pereira-Silva, Gean Carlo ; de Jesus, Beatriz de Barros Gonçalves ; Grinsztejn, Beatriz ; de Oliveira, Douglas Mathias ; Lopes-Cardoso E Souza, Carlos A ; Pedro, Renata Saraiva ; de Sousa Maia, Maria de Lourdes ; Amorim Filho, Luiz ; Teixeira, Gabriellen Vitiello ; Rozini, Stephane Vicente ; Bozza, Patricia T ; Bokel, Joanna ; Saraiva, Elvira M ; Kegele Lignani, Letícia ; Palhinha, Lohanna ; Mendes-de-Almeida, Daniela P ; Martins-Gonçalves, Remy ; Hoagland, Brenda ; de Azevedo-Quintanilha, Isaclaudia Gomes ; Hottz, Eugenio D ; Campos, Mariana M ; Mouta Nunes de Oliveira, Patricia

BACKGROUND:

Although rare, vaccine-induced thrombotic thrombocytopenia (VITT) following adenoviral vector COVID-19 vaccination is a concerning and often severe adverse effect of vaccination. The generation of high antiplatelet factor 4 antibody titers promotes the formation of immune complexes capable of activating platelets and neutrophils through FcγRIIa.

OBJECTIVES:

Given that platelet-leukocyte aggregate formation and inflammasome activation are common features of thromboinflammatory diseases, we aimed to evaluate if these are also features of VITT.

METHODS:

Samples from a cohort of 57 postvaccination thrombosis patients and 28 age- and sex-matched unvaccinated individuals were used for ex vivo investigation of platelet-leukocyte aggregate formation and inflammasome activation.

RESULTS:

Patients with clinical features of VITT presented elevated levels of activated caspase-1, interleukin-18, and interleukin-1β in the plasma. We also found that soluble factors in the plasma of VITT patients induce the formation of platelet-neutrophil aggregates but not platelet-monocyte or platelet T-cell aggregates, which are associated with increased caspase-1 activation in neutrophils ex vivo. Platelet-neutrophil aggregate formation was prevented through blockage of FcγRIIa with the neutralizing antibody IV.3 and through blockage of P-selectin or integrin α_IIbβ₃, also inhibiting caspase-1 activation. Additionally, MCC950, an NLRP3 inflammasome inhibitor, blocked caspase-1 activation.

CONCLUSION:

Taken together, these data show that VITT plasma induces platelet-neutrophil aggregate formation in a FcγRIIa-dependent manner and that platelet-neutrophil interactions may contribute to thromboinflammation in VITT patients by supporting NLRP3 inflammasome activation. These data shed light on novel immunopathological events associated with inflammation and thrombosis in VITT patients.

100 Deals associated with NLRP3 inflammasome inhibitor(Exscientia/University of Oxford)

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