Target Cell Activation of a Structurally Novel NOD-Like Receptor Pyrin Domain-Containing Protein 3 Inhibitor NT-0796 Enhances PotencyS

被引:5
|
作者
Smolak, Pamela [2 ]
Nguyen, MyTrang [1 ]
Diamond, Christine [2 ]
Wescott, Heather [2 ]
Doedens, John R. [2 ]
Schooley, Kenneth [2 ]
Snouwaert, John N. [1 ]
Bock, Mark G. [4 ]
Harrison, David [3 ]
Watt, Alan P. [2 ]
Koller, Beverly H. [1 ]
Gabel, Christopher A. [2 ,5 ]
机构
[1] Univ N Carolina, Dept Genet, Chapel Hill, NC USA
[2] Nodthera, Seattle, WA USA
[3] Nodthera, Cambridge, England
[4] Nodthera, Boston, MA USA
[5] Nodthera Inc, 454 N 34th St, Seattle, WA 98103 USA
来源
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2024年 / 388卷 / 03期
关键词
NLRP3; INFLAMMASOME; HUMAN CARBOXYLESTERASES; CYNOMOLGUS MONKEY; EXPRESSION; ESTERASE; INTERLEUKIN-1-BETA; SEQUENCE; CASPASES; PRODRUGS; PHARMACOLOGY;
D O I
10.1124/jpet.123.001941
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The NOD -like receptor pyrin domain -containing protein 3 (NLRP3) inflammasome is a central regulator of innate immunity, essential for processing and release of interleukin-1b and pyroptotic cell death. As endogenous NLRP3 activating triggers are hallmarks of many human chronic inflammatory diseases, inhibition of NLRP3 has emerged as a therapeutic target. Here we identify NDT-19795 as a novel carboxylic acid -containing NLRP3 activation inhibitor in both human and mouse monocytes and macrophages. Remarkably, conversion of the carboxylate to an isopropyl -ester (NT0796) greatly enhances NLRP3 inhibitory potency in human monocytes. This increase is attributed to the ester -containing pharmacophore being more cell -penetrant than the acid species and, once internalized, the ester being metabolized to NDT-19795 by carboxylesterase-1 (CES-1). Mouse macrophages do not express CES-1, and NT -0796 is ineffective in these cells. Mice also contain plasma esterase (Ces1c) activity which is absent in humans. To create a more human -like model, we generated a mouse line in which the genome was modified, removing Ces1c and replacing this segment of DNA with the human CES-1 gene driven by a mononuclear phagocyte -specific promoter. We show human CES-1 presence in monocytes/macrophages increases the ability of NT -0796 to inhibit NLRP3 activation both in vitro and in vivo. As NLRP3 is widely expressed by monocytes/macrophages, the coexistence of CES-1 in these same cells affords a unique opportunity to direct ester -containing NLRP3 inhibitors precisely to target cells of interest. Profiling NT -0796 in mice humanized with respect to CES-1 biology enables critical modeling of the pharmacokinetics and pharmacodynamics of this novel therapeutic candidate. SIGNIFICANCE STATEMENT Inhibition of NLRP3 represents a desirable therapeutic strategy for the treatment of multiple human disorders. In this study pharmacological properties of a structurally -novel, ester -containing NLRP3 inhibitor NT -0796 are characterized. To study pharmacodynamics of NT -0796 in vivo, a mouse line was engineered possessing more human -like traits with respect to carboxylesterase biology. In the context of these hCES-1 mice, NT -0796 serves as a more effective inhibitor of NLRP3 activation than the corresponding acid, highlighting the full translational potential of the ester strategy.
引用
收藏
页码:798 / 812
页数:15
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