PROTAC targeting cyclophilin A controls virus-induced cytokine storm.
PROTAC targeting cyclophilin A controls virus-induced cytokine storm.
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DOI：
10.1016/j.isci.2023.107535
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发表时间：
2023-09-15
期刊：
影响因子：
5.8
通讯作者：
Sun, Lei
中科院分区：
文献类型：
--
作者：
Li, Heqiao;Yang, Wenxian;Li, Huizi;Bai, Xiaoyuan;Zhang, He;Fan, Wenhui;Liu, Wenjun;Sun, Lei
由病毒引起的细胞因子风暴与升高的细胞因子水平和不受控制的炎症反应相关，可导致急性呼吸窘迫综合征。目前的抗病毒疗法不足以预防或治疗这些并发症。亲环素A（Cyclophilin A，CypA）是调节多种细胞因子产生的关键因子，可能成为细胞因子风暴的潜在治疗靶点。在此，设计了三种靶向CypA的蛋白水解靶向嵌合体（PROTAC）。这些PROTAC与CypA结合，增强其泛素化，并促进其在细胞系和小鼠器官中的降解。在乙型流感病毒（IBV）感染期间，PROTAC介导的CypA耗竭减少了A549细胞中P65磷酸化和NF-κ B介导的促炎细胞因子产生。此外，靶向CypA的Comp-K抑制支气管肺泡灌洗液中促炎细胞因子的过度分泌，减少肺损伤，并提高IBV感染小鼠的存活率。总的来说，我们提供靶向CypA的PROTAC，这是控制细胞因子风暴的潜在候选者。PROTAC与CypA结合并促进其泛素化介导的降解PROTAC在病毒感染期间消除细胞因子风暴PROTAC减轻肺损伤并提高IBV感染小鼠的存活率免疫学;分子生物学;病毒学
Cytokine storms caused by viruses are associated with elevated cytokine levels and uncontrolled inflammatory responses that can lead to acute respiratory distress syndrome. Current antiviral therapies are not sufficient to prevent or treat these complications. Cyclophilin A (CypA) is a key factor that regulates the production of multiple cytokines and could be a potential therapeutic target for cytokine storms. Here, three proteolysis targeting chimeras (PROTACs) targeting CypA were designed. These PROTACs bind to CypA, enhance its ubiquitination, and promote its degradation in both cell lines and mouse organs. During influenza B virus (IBV) infection, PROTAC-mediated CypA depletion reduces P65 phosphorylation and NF-κB-mediated proinflammatory cytokine production in A549 cells. Moreover, Comp-K targeting CypA suppresses excessive secretion of proinflammatory cytokines in bronchoalveolar lavage fluid, reduces lung injury, and enhances survival rates of IBV-infected mice. Collectively, we provide PROTACs targeting CypA, which are potential candidates for the control of cytokine storms. PROTAC binds to CypA and promotes its ubiquitination-mediated degradation PROTAC alleviates cytokine storm during virus infection PROTAC relieves lung injury and enhances survival rates of IBV-infected mice Immunology; Molecular biology; Virology
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DOI：
10.3390/v13071362
发表时间：
2021-07-14
期刊：
Viruses
影响因子：
--
作者：
Gu Y;Zuo X;Zhang S;Ouyang Z;Jiang S;Wang F;Wang G
通讯作者：
Wang G
影响因子：
120.7
作者：
Caricchio, Roberto;Abbate, Antonio;Noviello, Stephanie
通讯作者：
Noviello, Stephanie
影响因子：
3.7
作者：
Fenizia C;Galbiati S;Vanetti C;Vago R;Clerici M;Tacchetti C;Daniele T
通讯作者：
Daniele T
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
4.4
作者：
Arora, K;Gwinn, WM;Constant, SL
通讯作者：
Constant, SL