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Biochemical and Biophysical Research Communications, 2020.523(2), 368-374, DOI: https://doi.org/10.1016/j.bbrc.2019.12.029
Identification of novel compounds against Tat-mediated human immunodeficiency virus-1 tranion by high-throughput functional screening assay
YoungHyun Shin, Hong Gi Kim; Chul Min Park; Min Suk Choi; Dong-Eun Kim; Byeong-Sun Choi; Kisoon Kim; Cheol-Hee Yoon
Trans-activator (Tat)-mediated human immunodeficiency virus type 1 (HIV-1) tranion is essential for the replication of HIV-1 and is considered a potent therapeutic target for HIV-1 inhibition. In this study, the Library of Pharmacologically Active Compounds (LOPAC1280) was screened using our dualreporter screening system for repositioning as Tat-inhibitory compounds. Consequently, two compounds were found to be potent, with low cytotoxicity. Of these two compounds, Roscovitine (CYC202) is already known to be a Tat inhibitor, while gemcitabine has been newly identified as an inhibitor of Tatmediated tranion linked to viral production and replication. In an additional screening using the ribonucleoside analogues of gemcitabine, two analogues (20-C-methylcytidine and 3-deazauridine) showed a specific Tat-inhibitory effect linked to their anti-HIV-1 activity. Interestingly, these compounds did not affect Tat protein directly, while the mechanism underlying their inhibition of Tat-mediated tranion was linked to pyrimidine biosynthesis, rather than to alteration of the dNTP pool, influenced by the inhibition of ribonucleotide reductase. Taken together, the proposed functional screening system is a useful tool for the identification of inhibitors of Tat-mediated HIV-1 tranion from among a large number of compounds, and the inhibitory effect of HIV-1 tranion by gemcitabine and its analogues may suggest a strategy for developing a new class of therapeutic anti-HIV drugs.
- DOI: https://doi.org/10.1016/j.bbrc.2019.12.029
- ISBN or ISSN: 0006-291X
- 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
- This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.