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Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1

The “shock and kill” strategy might be a promising therapeutic approach for HIV/AIDS due to the existence of latent viral reservoirs. A major challenge of the “shock and kill” strategy arises from the general lack of clinically effective latency-reversing agents (LRAs). The 2-methylquinoline derivat...

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Autores principales: Ao, Mingtao, Pan, Zhenrui, Qian, Yuqing, Tang, Bowen, Feng, Zeming, Fang, Hua, Wu, Zhen, Chen, Jingwei, Xue, Yuhua, Fang, Meijuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9080425/
https://www.ncbi.nlm.nih.gov/pubmed/35539279
http://dx.doi.org/10.1039/c8ra01216d
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author Ao, Mingtao
Pan, Zhenrui
Qian, Yuqing
Tang, Bowen
Feng, Zeming
Fang, Hua
Wu, Zhen
Chen, Jingwei
Xue, Yuhua
Fang, Meijuan
author_facet Ao, Mingtao
Pan, Zhenrui
Qian, Yuqing
Tang, Bowen
Feng, Zeming
Fang, Hua
Wu, Zhen
Chen, Jingwei
Xue, Yuhua
Fang, Meijuan
author_sort Ao, Mingtao
collection PubMed
description The “shock and kill” strategy might be a promising therapeutic approach for HIV/AIDS due to the existence of latent viral reservoirs. A major challenge of the “shock and kill” strategy arises from the general lack of clinically effective latency-reversing agents (LRAs). The 2-methylquinoline derivative, antiviral 6 (AV6) has been reported to induce latent HIV-1 expression and act synergistically with a HDAC inhibitor VA to reverse HIV latency. We report herein the design and identification of AV6 analogues which possess the zinc-binding group of HDAC inhibitors and have dual acting mechanism for the reactivation of HIV-1 from latency. Evaluation of compounds for the reactivation of HIV-1 latency identified two excellent active compounds 12c and 12d. Further bioassays revealed that these two compounds reactivated latent HIV-1 through dual mechanism, the inhibition of HDACs and NFAT-required for early HIV-1 gene expression. Additionally, it was found that 12c and 12d could reactivate HIV-1 transcription by releasing P-TEFb from the inactive complex 7SK snRNP. At last, molecular docking identified their orientation and binding interactions at the active site of HDAC2. This experimental data suggests that 12c and 12d can be served as effective HIV-1 LRAs which can be taken up for further studies.
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spelling pubmed-90804252022-05-09 Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1 Ao, Mingtao Pan, Zhenrui Qian, Yuqing Tang, Bowen Feng, Zeming Fang, Hua Wu, Zhen Chen, Jingwei Xue, Yuhua Fang, Meijuan RSC Adv Chemistry The “shock and kill” strategy might be a promising therapeutic approach for HIV/AIDS due to the existence of latent viral reservoirs. A major challenge of the “shock and kill” strategy arises from the general lack of clinically effective latency-reversing agents (LRAs). The 2-methylquinoline derivative, antiviral 6 (AV6) has been reported to induce latent HIV-1 expression and act synergistically with a HDAC inhibitor VA to reverse HIV latency. We report herein the design and identification of AV6 analogues which possess the zinc-binding group of HDAC inhibitors and have dual acting mechanism for the reactivation of HIV-1 from latency. Evaluation of compounds for the reactivation of HIV-1 latency identified two excellent active compounds 12c and 12d. Further bioassays revealed that these two compounds reactivated latent HIV-1 through dual mechanism, the inhibition of HDACs and NFAT-required for early HIV-1 gene expression. Additionally, it was found that 12c and 12d could reactivate HIV-1 transcription by releasing P-TEFb from the inactive complex 7SK snRNP. At last, molecular docking identified their orientation and binding interactions at the active site of HDAC2. This experimental data suggests that 12c and 12d can be served as effective HIV-1 LRAs which can be taken up for further studies. The Royal Society of Chemistry 2018-05-11 /pmc/articles/PMC9080425/ /pubmed/35539279 http://dx.doi.org/10.1039/c8ra01216d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Ao, Mingtao
Pan, Zhenrui
Qian, Yuqing
Tang, Bowen
Feng, Zeming
Fang, Hua
Wu, Zhen
Chen, Jingwei
Xue, Yuhua
Fang, Meijuan
Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1
title Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1
title_full Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1
title_fullStr Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1
title_full_unstemmed Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1
title_short Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1
title_sort design, synthesis, and biological evaluation of av6 derivatives as novel dual reactivators of latent hiv-1
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9080425/
https://www.ncbi.nlm.nih.gov/pubmed/35539279
http://dx.doi.org/10.1039/c8ra01216d
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