| Autor: |
Biby S; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States., Mondal P; 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., Xu Y; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States., Gomm A; 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., Kaur B; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States., Namme JN; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States., Wang C; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States., Tanzi RE; 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., Zhang S; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298, United States., Zhang C; 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. |
| Abstrakt: |
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. |
