UC Irvine Lab Studies NLRP3 Inflammasome for Inflammatory Disease Treatment Potential

IRVINE, CALIFORNIA - 16 APRIL 2020: Student Center and Visitor Center Building on the campus of the University of California Irvine, UCI. | Image Credit: © Steve Cukrov - stock.adobe.com

The laboratory of University of California, Irvine (UC Irvine) Charlie Dunlop School of Biological Sciences assistant professor Reginald McNulty has published research on the current drug candidates that target the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a protein complex that plays a central role in causing inflammation in response to infection or tissue damage. The research team has stated that it has discovered the first and only known drugs that bind directly to the pyrin domain (1).

No such drug has yet been approved by FDA despite years of investigation, according to a UC Irvine press release (1). And when left unchecked, the McNulty lab said, NLRP3 can contribute to chronic inflammatory diseases affecting millions globally—everything from arthritis to Alzheimer’s disease to rare genetic disorders—or otherwise damage the body rather than protecting it.

Shortcomings of current drugs

“The NLRP3 inflammasome is a key mediator of the innate immune response to pathogen infection or tissue damage,” McNulty said in the press release (1). “Some humans have mutations in NLRP3 that make them more susceptible to the plethora of disorders and diseases NLRP3 is involved in, ranging from autism and arthritis to liver disease. Yet there are currently no FDA-approved drugs that target it.”

McNulty’s team concluded that the present crop of candidates to treat it, their discovery excluded, falls short in numerous areas, such as poor targeting or unwanted side effects (1).

“A significant challenge is to design an NLRP3 inhibitor that doesn’t bind domains previously shown to have ill-desired off-target effects,” McNulty said (1). “We showed that the pyrin domain has a similar structure to human glycosylase, and that inhibitors targeting one could be repurposed to inhibit the other.”

A next-generation approach

The research team’s study, published online in Trends in Pharmacological Sciences, describes its design of molecules that resemble damaged pieces of DNA, using oxidized guanine, which were deployed to block NLRP3 at the pyrin domain, preventing it from jump-starting a series of reactions that result in inflammation (1,2).

With an eye on next-generation anti-inflammatory therapies, the lab is now using cryo-electron microscopy to visualize the binding of the molecules to the pyrin domain, with safety and efficacy testing in a clinical setting being the next step (1).

“Progress in clinical trials will be key in advancing our understanding of mitigating inflammasome-based diseases,” McNulty said (1).

Investigation into the NLRP3 inflammasome can be lucrative. In September 2022, Novo Nordisk paid nearly $700 million for exclusive, worldwide rights to develop and commercialize candidates from Ventus Therapeutics’ portfolio of peripherally restricted NLRP3 inhibitors (3). At that time, Ventus’ lead NLRP3 inhibitor program had been indicated for nonalcoholic steatohepatitis, chronic kidney disease, and several other cardiometabolic conditions. Ventus retained the right to develop NLRP3 inhibitors for certain systemic diseases, including specific inflammatory and respiratory diseases, as well as worldwide rights to the company’s brain-penetrant NLRP3 inhibitor program.

References

1. University of California, Irvine. UC Irvine Researchers Explore Promising New Pathway for Treating Inflammatory Diseases. Press Release. May 15, 2025.
2. Cabral, J. E.; Wu, A.; Zhou, H.; Pham, M. A.; Lin, S.; and McNulty, R. Targeting the NLRP3 Inflammasome for Inflammatory Disease Therapy. Trends Pharmacol. Sci. 2025, online. DOI: 10.1016/j.tips.2025.04.007
3. Ventus Therapeutics. Ventus Therapeutics Enters Exclusive Development and License Agreement with Novo Nordisk for NLRP3 Inhibitor Program. Press Release. Sept. 29, 2022.