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糖仿制剂作为针对高炎症的E-和P-选择蛋白对抗剂Sialyl Lewis

Mathieu Joyal¹, Ryan D Simard^2,3, Wael Maharsy¹

¹Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.

ACS medicinal chemistry letters

|January 15, 2025

概括

新的糖仿制药阻断了P-和E-选择因子的相互作用,减少了超炎症模型中的免疫细胞招募. 这些化合物具有管理炎症性疾病的潜力,如败血症和严重的COVID-19.

科学领域:

免疫学免疫学免疫学
药理学药理学是指药理学的学科.
生物化学生物化学

背景情况:

炎症性疾病 (如败血症,严重的COVID-19) 会导致免疫功能障碍,细胞因子风暴和高死亡率.
过度的免疫细胞流入和随后的免疫抑制有助于器官损伤和不良结果.
针对白细胞-P-选择因子相互作用提供了一种可控免疫抑制的策略.

研究的目的:

发现和描述针对P-和E-selectin的新型免疫调节剂.
评估这些化合物的有效性,以减少免疫细胞的招募in vivo超炎症模型.

主要方法:

设计和合成sialylLewis^x糖仿制剂 (化合物12和13) 与一个四醇碳酸生物.
对P-和E-选择素的结合和PSGL-1相互作用的阻断的评估.
在超炎症模型中的体内评估,以量化免疫细胞群.

主要成果:

化合物12和13有效地结合P-和E-选择素,抑制PSGL-1相互作用.
在体内给药显著降低了免疫细胞的招募,包括中性粒细胞,CD11b+,单细胞/巨细胞和PSGL-1+细胞.
在多个时间点证明了关键炎症细胞标记物的减少.

结论:

利易斯糖仿制剂 (12和13) 是选择性中介白细胞粘附的强有力的抑制剂.
这些化合物显示出作为治疗治疗系统性炎症反应综合征和相关超炎症状况的治疗线索的前景.

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