國家衛生研究院 NHRI:Item 3990099045/14071
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    题名: Tyrphostin AG1024 suppresses coronaviral replication by downregulating JAK1 via an IR/IGF-1R independent proteolysis mediated by Ndfip1/2_NEDD4-like E3 ligase itch
    作者: Yang, CW;Lee, YZ;Hsu, HY;Zhao, GH;Lee, SJ
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: JAK1 depletion or downregulation was previously reported to account for coronavirus inhibition. Here, we found that AG1024, an IR (insulin receptor) and IGF-1R (insulin-like growth factor 1 receptor) inhibitor, diminishes JAK1 protein levels and exerts anti-coronaviral activities with EC(50) values of 5.2 ± 0.3 μM against transmissible gastroenteritis coronavirus (TGEV) and 4.3 ± 0.3 μM against human flu coronavirus OC43. However, although the IR and IGF-1R signaling pathways are activated by insulin or IGF-1 in swine testis cells, they are not triggered upon TGEV infection. AG1024, therefore, inhibits coronaviral replication and downregulates JAK1 protein levels independently of IR and IGF-1R. Moreover, JAK1 proteolysis caused by AG1024 was found through activation of upstream Ndfip1/2 and its effector NEDD4-like E3 ligase Itch. In addition, ouabain, which was reported to mediate JAK1 proteolysis causing anti-coronaviral activity by activation of Ndfip1/2 and NEDD4 E3 ligase, additively inhibited anti-coronaviral activity and JAK1 diminishment in combination with AG1024. This study provides novel insights into the pharmacological effects of AG1024 and Itch E3 ligase mediated JAK1 proteolysis and identified Ndfip1/2 as a cognate effector for JAK1 proteolysis via the diversified E3 ligases NEDD4 and NEDD4-like Itch. These findings are expected to provide valued information for the future development of anti-viral agents.
    日期: 2022-02-17
    關聯: Pharmaceuticals. 2022 Feb 17;15(2):Article number 241.
    Link to: http://dx.doi.org/10.3390/ph15020241
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1424-8247&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000826771400001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85125190819
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