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Selectively T cell phosphorylation activation of azvudine in the thymus tissue with immune protection effect
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2024-03-30 , DOI: 10.1016/j.apsb.2024.03.032 Ning Sheng 1 , Rui Li 2 , Yang Li 1 , Zhe Wang 1 , Lulu Wang 2 , Yuhuan Li 2 , Jinlan Zhang 1 , Jiandong Jiang 1, 2
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2024-03-30 , DOI: 10.1016/j.apsb.2024.03.032 Ning Sheng 1 , Rui Li 2 , Yang Li 1 , Zhe Wang 1 , Lulu Wang 2 , Yuhuan Li 2 , Jinlan Zhang 1 , Jiandong Jiang 1, 2
Affiliation
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Thymus is the important immune organ, responsible for T cell development and differentiation. The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors. Azvudine, also known as FNC, is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients. In this study, single-cell transcriptome, proteomics, and parallel reaction monitoring (PRM) were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus. The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC. Key enzymes involved in the FNC phosphorylation process, such as Dck, Cmpk1, and Nme2, were highly expressed in CD4+ T cells, CD8+ T cells, and DP (CD4+ CD8+) cells. Additionally, FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases, phosphoribosyl transferases, and deaminases, respectively. The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC, and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties, as an important factor during antiviral drug design.
中文翻译：
胸腺组织中阿兹夫定选择性T细胞磷酸化激活具有免疫保护作用
胸腺是重要的免疫器官，负责T细胞的发育和分化。与幸存者相比，死于 COVID-19 的患者的循环 T 计数较低。 Azvudine，也称为 FNC，是一种胸腺归巢抗 SARS-CoV-2 药物，用于治疗 COVID-19 患者。在本研究中，应用单细胞转录组、蛋白质组和平行反应监测（PRM）来深入了解大鼠和SARS-CoV-2恒河猴胸腺中FNC的激活过程。结果表明，胸腺免疫细胞对FNC等胞苷类似物药物具有强大的代谢能力。 FNC磷酸化过程中涉及的关键酶，如Dck、Cmpk1和Nme2，在CD4+ T细胞、CD8+ T细胞和DP（CD4+ CD8+）细胞中高表达。此外，FNC 可以上调各种细胞类型中的多种磷酸化激酶，同时分别下调磷酸酶、磷酸核糖基转移酶和脱氨酶。胸腺对胞苷类似物药物FNC强大的磷酸化能力，以及FNC对NAs代谢系统的激活作用，可能有助于其在胸腺中的富集和免疫保护作用。这表明在评估 NA 药物特性时考虑磷酸化激酶的表达水平至关重要，作为抗病毒药物设计中的一个重要因素。
更新日期：2024-03-30
中文翻译：
胸腺组织中阿兹夫定选择性T细胞磷酸化激活具有免疫保护作用
胸腺是重要的免疫器官，负责T细胞的发育和分化。与幸存者相比，死于 COVID-19 的患者的循环 T 计数较低。 Azvudine，也称为 FNC，是一种胸腺归巢抗 SARS-CoV-2 药物，用于治疗 COVID-19 患者。在本研究中，应用单细胞转录组、蛋白质组和平行反应监测（PRM）来深入了解大鼠和SARS-CoV-2恒河猴胸腺中FNC的激活过程。结果表明，胸腺免疫细胞对FNC等胞苷类似物药物具有强大的代谢能力。 FNC磷酸化过程中涉及的关键酶，如Dck、Cmpk1和Nme2，在CD4+ T细胞、CD8+ T细胞和DP（CD4+ CD8+）细胞中高表达。此外，FNC 可以上调各种细胞类型中的多种磷酸化激酶，同时分别下调磷酸酶、磷酸核糖基转移酶和脱氨酶。胸腺对胞苷类似物药物FNC强大的磷酸化能力，以及FNC对NAs代谢系统的激活作用，可能有助于其在胸腺中的富集和免疫保护作用。这表明在评估 NA 药物特性时考虑磷酸化激酶的表达水平至关重要，作为抗病毒药物设计中的一个重要因素。
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