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Virologica Sinica, 2020.N, 0-0, DOI: https://doi.org/10.1007/s12250-020-00274-7
Identification of Aristolactam Derivatives That Act as Inhibitors of Human Immunodeficiency Virus Type 1 Infection and Replication by Targeting Tat-Mediated Viral Tranion
YoungHyun Shin, Chul Min Park; Hong Gi Kim; Dong-Eun Kim; Min Suk Choi; Jeong-ah Kim; Byeong-Sun Choi; Cheol-Hee Yoon
Despite the success of antiretroviral therapy (ART), efforts to develop new classes of antiviral agents have been hampered by the emergence of drug resistance. Dibenzo-indole-bearing aristolactams are compounds that have been isolated from various plants species and which show several clinically relevant effects, including anti-inflammatory, antiplatelet, and antimycobacterial actions. However, the effect of these compounds on human immunodeficiency virus type 1 (HIV-1) infection has not yet been studied. In this study, we discovered an aristolactamderivative bearing dibenzo[cd,f]indol-4(5H)-one that had a potent anti-HIV-1 effect. A structure-activity relationship (SAR) study using nine synthetic derivatives of aristolactam identified the differing effects of residue substitutions on the inhibition of HIV-1 infection and cell viability. Among the compounds tested, 1,2,8,9-tetramethoxy-5-(2-(piperidin-1-yl)ethyl)-dibenzo[cd,f]indol-4(5H)-one (Compound 2) exhibited the most potent activity by inhibiting HIV-1 infection with a half-maximal inhibitory concentration (IC50) of 1.03 lmol/L and a half-maximal cytotoxic concentration (CC50) of 16.91 lmol/L (selectivity index, 16.45). The inhibitory effect of the compounds on HIV-1 infection was linked to inhibition of the viral replication cycle. Mode-of-action studies showed that the aristolactam derivatives did not affect reverse tranion or integration; instead, they specifically inhibited Tat-mediated viral tranion. Taken together, these findings show that several aristolactam derivatives impaired HIV-1 infection by inhibiting the activity of Tat-mediated viral tranion, and suggest that these derivatives could be antiviral drug candidates.
- DOI: https://doi.org/10.1007/s12250-020-00274-7
- ISBN or ISSN: 1674-0769
- 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
- This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.