Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1784702783604129792 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9080425 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT aomingtao designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT panzhenrui designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT qianyuqing designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT tangbowen designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT fengzeming designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT fanghua designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT wuzhen designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT chenjingwei designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT xueyuhua designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 AT fangmeijuan designsynthesisandbiologicalevaluationofav6derivativesasnoveldualreactivatorsoflatenthiv1 |