# Development of NLRP3 inflammasome inhibitors towards Alzheimer's disease

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $462,952

## Abstract

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). One of the pathologies associated with COVID-19 is pneumonia that quickly leads
to acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) and ultimately patient death. Recent
studies suggested a critical role of the NLRP3 inflammasome, a multiprotein platform that tightly regulates the
innate immune response, in the development of ARDS/ALI in COVID-19. Dysregulation of the NLRP3
inflammasome is responsible for the excessive production of pro-inflammatory interleukin (IL)-1β and IL-18, whch
is involved in the uncontrolled inflammatory responses and cytokine storm. Therefore, development of NLRP3
inhibitors (NLRP3is) represents a novel approach to mitigating ARDS/ALI in COVID-19 patients. Recently, we
developed novel small molecule NLRP3is that blocks the assembly and activation of the NLRP3 inflammasome,
resulting in inhibition of IL-1β production both in vitro and in vivo. Studies in animal models of neurodegenerative
disorders demonstrated target engagement and in vivo efficacy, thus providing proof-of-concept for further
developing NLRP3is as therapeutics. Notably, our studies in experimental autoimmune encephalomyelitis (EAE),
a mouse model of multiple sclerosis in which excessive inflammation is one of the prominent pathologies, showed
that the lead inhibitor reduced the severity of EAE both preventively and therapeutically. Treatment with this lead
compound also substantially reduced the type 17-helper T (Th17) cells that produce IL-17, indicating its potential
in restraining uncontrolled inflammation. The central hypothesis of this proposal is that aberrant activation of
NLRP3 inflammasome contributes to the induction of cytokine storm and development of ARDS/ALI in COVID-
19, and its pharmacological inhibition with NLRP3is will prevent and reduce ARDS. With the current R01 support
(R01AG058673), we have successfully developed selective NLRP3is from novel chemical scaffolds and
identified lead compounds with improved inhibitory potency and druggability. We also identified compounds as
non-selective NLRP3is to reduce the production of multiple pro-inflammatory cytokines including IL-1β, IL-6 and
TNF-alpha. The goal of this supplement project is to test selective and non-selective NLRP3is as potential
treatments for ARDS in COVID-19. Two specific aims are proposed in this application. In Aim 1, analogs based
on the newly identified chemical scaffolds will be designed and synthesized to identify candidates for in vivo
studies. In Aim 2, the top candidate inhibitors will be studied to confirm the therapeutic efficacy to mitigate lung
injury in a mouse model of ARDS. The proposed research is highly significant because successful development
of novel NLRP3is may provide promising candidates with translational potential for clinical management of
COVID-19.

## Key facts

- **NIH application ID:** 10149565
- **Project number:** 3R01AG058673-03S1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Xiang-Yang Shawn Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,952
- **Award type:** 3
- **Project period:** 2018-03-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149565

## Citation

> US National Institutes of Health, RePORTER application 10149565, Development of NLRP3 inflammasome inhibitors towards Alzheimer's disease (3R01AG058673-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10149565. Licensed CC0.

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