2-thio-6-azauridine inhibits Vpu mediated BST-2 degradation

Springer Science and Business Media LLC - Tập 13 - Trang 1-14 - 2016
Quan Zhang1, Zeyun Mi1,2, Yuming Huang3, Ling Ma1, Jiwei Ding1, Jing Wang1, Yongxin Zhang1, Yang chen1, Jinming Zhou1, Fei Guo4, Xiaoyu Li1, Shan Cen1
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China
3Beijing Ditan Hospital, Capital Medical University, Beijing, China
4Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Tóm tắt

BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the newly formed virions onto the host cell surface. Human Immunodeficiency Virus-1 (HIV-1) encodes an accessory protein Vpu that antagonizes BST-2 by down-regulating BST-2 from the cell surface. Using a cell-based ELISA screening system, we have discovered a lead compound, 2-thio-6-azauridine, that restores cell surface BST-2 level in the presence of Vpu. This compound has no effect on the expression of BST-2 and Vpu, but inhibits Vpu-mediated BST-2 down-regulation and exerts no effect on Vpu-induced down-regulation of CD4 or KSHV K5 protein induced BST-2 down-regulation. 2-thio-6-azauridine suppresses HIV-1 production in a BST-2-dependent manner. Further results indicate that 2-thio-6-azauridine does not interrupt the interaction of BST-2 with Vpu and β-TrCP2, but decreases BST-2 ubiquitination. Our study demonstrates the feasibility of using small molecules to target Vpu function and sensitize wild type HIV-1 to BST-2-mediated host restriction.

Tài liệu tham khảo

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