Biby Savannah, Mondal Prasenjit, Xu Yiming, Gomm Ashley, Kaur Baljit, Namme Jannatun N, Wang Changning, Tanzi Rudolph E, Zhang Shijun, Zhang Can
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
ACS Chem Neurosci. 2024 Oct 2;15(19):3576-3586. doi: 10.1021/acschemneuro.4c00512. Epub 2024 Sep 19.
Considerable evidence indicates that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays key roles in human pathophysiology, suggesting it as a potential drug target. Currently, studies have yet to develop compounds that are promising therapeutics in the clinic by targeting the NLRP3 inflammasome. Herein, we aim to further biologically characterize a previously identified small-molecule inhibitor of the NLRP3 inflammasome from our group, YM-I-26, to confirm its functional activities. We showed that YM-I-26 is highly selective toward the NLRP3 inflammasome and binds to NLRP3 directly. A systemic analysis revealed YM-I-26 with inflammation-related and immunomodulatory activities by the Eurofins BioMAP Diversity PLUS panel. In addition, studies using the mouse microglia BV2 cell model demonstrated that YM-I-26 is not cytotoxic, improved the phagocytotic functions of BV2 cells toward beta-amyloid, and suppressed the production of cytokines of IL-1β and IL-10 upon the activation of the NLRP3 inflammasome. Collectively, our studies support the functional activities of YM-I-26 as a NLRP3 inhibitor in physiologically relevant cell models, and warrant future studies of YM-I-26 and its analogs to advance the drug development as potential therapeutics.
大量证据表明，含吡咯结构域的NOD样受体家族3（NLRP3）炎性小体在人类病理生理学中起关键作用，这表明它是一个潜在的药物靶点。目前，针对NLRP3炎性小体的化合物研究尚未开发出有望用于临床治疗的药物。在此，我们旨在进一步从生物学角度表征我们团队之前鉴定出的一种NLRP3炎性小体小分子抑制剂YM-I-26，以确认其功能活性。我们发现YM-I-26对NLRP3炎性小体具有高度选择性，并能直接与NLRP3结合。通过欧洲药典生物图谱多样性增强板进行的系统分析揭示了YM-I-26具有炎症相关和免疫调节活性。此外，使用小鼠小胶质细胞BV2细胞模型的研究表明，YM-I-26没有细胞毒性，改善了BV2细胞对β-淀粉样蛋白的吞噬功能，并在NLRP3炎性小体激活后抑制了IL-1β和IL-10细胞因子的产生。总体而言，我们的研究支持了YM-I-26作为NLRP3抑制剂在生理相关细胞模型中的功能活性，并为未来对YM-I-26及其类似物的研究提供了依据，以推动其作为潜在治疗药物的开发。
