作者: Zhang, Shuang-Shuang ; Zhang, Guo-Lin ; Wei, Kun ; Chen, Da-Peng ; Dong, Jian-Yi ; He, Li-Heng ; Qiu, Yang ; Guo, Xin-Rui ; Zhou, Zi-Juan ; Wang, Jing-Yu ; Jiang, Hao-Zheng ; Sun, Yi-Ning

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg^-1·d^-1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1β. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1β, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

2024-05-24·Current Computer-Aided Drug Design

Structural Insight into the Binding Pattern and Interaction Mechanism of Antagonist MCC950 and Agonist BMS986299 with NLRP3 by Molecular Dynamics Simulation

Article

作者: Min, Zhenli ; Xiong, Xin ; Zhang, Ruifeng

Objective:::

The NLRP3 inflammasome mediates a range of inflammatory responses that are associated with an increasing number of pathological mechanisms. Over-activation of NLRP3 can exacerbate many diseases. However, NLRP3 antagonists have significant therapeutic potential. Moreover, NLRP3 plays an important role in limiting the growth and spread of some tumors, and NLRP3 agonists also have clinical value. MCC950 and BMS986299 are an antagonist and agonist of NLRP3, respectively. In light of the important clinical applications of NLRP3, especially for NLRP3 inhibitors, a computational method was used to investigate the interaction modes of MCC950 and BMS986299 with NLRP3 in order to design and develop more potent NLRP3 regulators.

Methods:::

In this study, the conformational behaviors of NLRP3 bound to the antagonist MCC950 in an inactive state and the agonist BMS986299 in an active state were investigated using 200 ns equilibrium all-atom molecular dynamics (MD) simulations, and then the analyses of the MD trajectories (RMSD, Rg, RMSF, SASA, PCA, and DCCM) were carried out to explore the mechanism of the antagonist and agonist on NLRP3 in the two different states.

Results:::

The RMSD, RMSF, Rg, SASA, and PCA analyses indicated that NLRP3 was more dispersive and less energetically stable in the active state than in the inactive state and that MCC950 significantly reduced the fluctuations of the interactive residues while BMS986299 did not. The antagonist MCC950 interacted with residues mainly in the NBD, HD1, WHD, and HD2 domains of NLRP3, whereas the agonist BMS986299 mainly in the NBD and WHD of NLRP3. Additionally, both compounds did not interact with residues located in the FISNA domain. The conformation of the FISNA domain appeared to change significantly when NLRP3 was translated from an inactive state to an active state.

Conclusion:::

The antagonist may interact with residues mainly in the NBD, HD1, WHD, and HD2 domains, and the agonist may interact in the NBD and WHD domains. Our study provided new insights into the development of NLRP3 regulators.

bioRxiv : the preprint server for biology

Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists

作者: Paulo, Joao A ; Hollingsworth, L Robert ; Harper, J Wade ; Veeraraghavan, Priya ; Rauch, Isabella

ABSTRACT:

Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 3 (NLRP3) is an innate immune sensor that forms an inflammasome in response to various cellular stressors. Gain-of-function mutations in NLRP3 cause autoinflammatory diseases and NLRP3 signalling itself exacerbates the pathogenesis of many other human diseases. Despite considerable therapeutic interest, the primary drivers of NLRP3 activation remain controversial due to the diverse array of signals that are integrated through NLRP3. Here, we mapped subcellular proteome changes to lysosomes, mitochondrion, EEA1-positive endosomes, and Golgi caused by the NLRP3 inflammasome agonists nigericin and CL097. We identified several common disruptions to retrograde trafficking pathways, including COPI and Shiga toxin-related transport, in line with recent studies. We further characterized mouse NLRP3 trafficking throughout its activation using temporal proximity proteomics, which supports a recent model of NLRP3 recruitment to endosomes during inflammasome activation. Collectively, these findings provide additional granularity to our understanding of the molecular events driving NLRP3 activation and serve as a valuable resource for cell biological research. We have made our proteomics data accessible through an open-access Shiny browser to facilitate future research within the community, available at:https://harperlab.connect.hms.harvard.edu/inflame/. We will display anonymous peer review for this manuscript onpubpub.org(https://harperlab.pubpub.org/pub/nlrp3/) rather than a traditional journal. Moreover, we invite community feedback on the pubpub version of this manuscript, and we will address criticisms accordingly.

项与 NLRP3 regulators(JMackem) 相关的新闻（医药）

2024-09-04

·BioSpace

Lilly Partner BioAge Files for IPO to Advance Obesity Candidate

iStock, JHVEPhoto BioAge will use the proceeds from the initial public offering to move its oral apelin receptor agonist azelaprag past its Phase III STRIDES study and into a registrational Phase III trial. BioAge Labs revealed its plans for an initial public offering on Tuesday, as it looks to capitalize on the red-hot obesity medication market. The California-based biotech has not yet announced how much it expects to raise, nor has it set a completion date for the initial public offering (IPO). Once completed, BioAge will trade on the Nasdaq Global Market under the ticker symbol BIOA. The biotech is also offering its underwriters—Goldman Sachs, Citi, Jefferies and Morgan Stanley—a 30-day option to purchase additional shares of its common stock at the IPO price, minus discounts and commissions. According to BioAge, the primary objective of its IPO is to increase the company’s “financial flexibility” as well as to provide additional capital for its operations. The biotech will use the proceeds to advance its lead candidate azelaprag past its Phase III STRIDES study and into a registrational Phase III trial. Designed to be orally available, azelaprag is a small molecule activator of the apelin receptor which could help “recapitulate many of the benefits of exercise,” according BioAge. Azelaprag works by mimicking apeline, a protein that the body secretes in response to exercise, helping to potentially boost patients’ basal metabolic rate and insulin sensitivity while also inhibiting inflammation and muscle atrophy. Currently, the biotech is running a Phase II study assessing azelaprag with Eli Lilly’s blockbuster incretin therapy tirzepatide to help lower body weight, while also improving body composition. Topline data from the study are expected in the third quarter of 2025. BioAge also has plans to launch a Phase II study of azelaprag with Novo Nordisk’s semaglutide next year. BioAge will use the IPO funds to start a proof-of-concept study of azelaprag in insulin sensitivity, with an eye toward expanding its indication. A chunk of the IPO raise will also go toward developing its NLRP3 blocker for neuroinflammation. Tuesday’s IPO announcement comes after BioAge in February 2024 announced that it raised $170 million in an oversubscribed Series D funding round. Lilly Ventures, the venture capital arm of Eli Lilly, participated in the financing round. Lilly is also partnered with BioAge for the biotech’s Phase II trial of azelaprag. With its IPO, BioAge joins three other biotechs that have recently announced plans to go public. Last month, MBX Biosciences revealed its Nasdaq bid , the proceeds from which will help support its chronic hypoparathyroidism program. Cancer-focused Bicara Therapeutics and immunology player Zenas Biopharma also revealed IPO plans.

临床2期IPO临床3期

100 项与 NLRP3 regulators(JMackem) 相关的药物交易

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