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Identification of Aristolactam Derivatives That Act as Inhibitors of Human Immunodeficiency Virus Type 1 Infection and Replication by Targeting Tat-Mediated Viral Transcription

  • RESEARCH ARTICLE
  • Published:
Virologica Sinica

Abstract

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 anti-mycobacterial 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 aristolactam derivative 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 μmol/L and a half-maximal cytotoxic concentration (CC50) of 16.91 μmol/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 transcription or integration; instead, they specifically inhibited Tat-mediated viral transcription. Taken together, these findings show that several aristolactam derivatives impaired HIV-1 infection by inhibiting the activity of Tat-mediated viral transcription, and suggest that these derivatives could be antiviral drug candidates.

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Acknowledgements

This work was supported by grants from the Korea National Institute of Health (Grant Number: 2019-NI-066-00 and 2020-ER5106-00).

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  1. YoungHyun Shin and Chul Min Park have contributed equally to this work.

Authors and Affiliations

  1. Division of Viral Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Heungdeok-gu, Cheongju-si, Chungbuk, 28159, Republic of Korea

    YoungHyun Shin, Dong-Eun Kim, Jeong-ah Kim, Byeong-Sun Choi & Cheol-Hee Yoon

  2. Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, 34114, Republic of Korea

    Chul Min Park, Hong Gi Kim & Min Suk Choi

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  1. YoungHyun Shin
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Contributions

CHY conceived the project. YS and CMP mainly conducted the experiments and participated in the drafting of the manuscript. HGK, MSC, DEK, BSC, KK discussed and analyzed the data. CHY wrote the manuscript. All of the authors have read and approved the final manuscript.

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Correspondence to Cheol-Hee Yoon.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Shin, Y., Park, C.M., Kim, H.G. et al. Identification of Aristolactam Derivatives That Act as Inhibitors of Human Immunodeficiency Virus Type 1 Infection and Replication by Targeting Tat-Mediated Viral Transcription. Virol. Sin. 36, 254–263 (2021). https://doi.org/10.1007/s12250-020-00274-7

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  • DOI: https://doi.org/10.1007/s12250-020-00274-7

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