Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1.
Design, synthesis, and biological evaluation of AV6 derivatives as novel dual reactivators of latent HIV-1.
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AV6 衍生物作为潜在 HIV-1 新型双重激活剂的设计、合成和生物学评价
DOI：
10.1039/c8ra01216d
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发表时间：
2018-05-09
期刊：
影响因子：
3.9
通讯作者：
Fang, Meijuan
中科院分区：
文献类型：
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作者：
Ao, Mingtao;Pan, Zhenrui;Qian, Yuqing;Tang, Bowen;Feng, Zeming;Fang, Hua;Wu, Zhen;Chen, Jingwei;Xue, Yuhua;Fang, Meijuan
由于潜伏病毒库的存在，“休克和杀伤”策略可能是一种很有前途的治疗HIV/AIDS的方法。“休克和杀伤”策略的一个主要挑战来自普遍缺乏临床有效的潜伏期逆转剂（LRAs）。据报道，2-甲基喹啉衍生物抗病毒6 （AV6）可诱导潜伏的HIV-1表达，并与HDAC抑制剂VA协同作用以逆转HIV潜伏期。我们在此报告了AV6类似物的设计和鉴定，这些类似物具有HDAC抑制剂的锌结合基团，并且具有双重作用机制，可以使HIV-1从潜伏中重新激活。对HIV-1潜伏期再激活化合物的评估鉴定出两种极好的活性化合物12c和12d。进一步的生物测定表明，这两种化合物通过双重机制重新激活潜伏的HIV-1，抑制hdac和早期HIV-1基因表达所需的nfat。此外，研究发现12c和12d可以通过释放无活性复合物7SK snRNP中的P-TEFb来重新激活HIV-1转录。最后，分子对接鉴定了它们在HDAC2活性位点的取向和结合相互作用。这一实验数据表明12c和12d可以作为有效的HIV-1 LRAs，可以进行进一步的研究。作为双作用HIV LRAs，化合物12c和12d可以通过nfat所需的机制激活潜伏的HIV-1，并作为组蛋白去乙酰化酶（HDAC）抑制剂。
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. As dual-acting HIV LRAs, compounds 12c and 12d could activate latent HIV-1 via the NFAT-required mechanism and as histone deacetylase (HDAC) inhibitors.
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影响因子：
1
作者：
Datta PK;Kaminski R;Hu W;Pirrone V;Sullivan NT;Nonnemacher MR;Dampier W;Wigdahl B;Khalili K
通讯作者：
Khalili K
影响因子：
7.3
作者：
Bourguet, Erika;Ozdarska, Katarzyna;Naassila, Mickael
通讯作者：
Naassila, Mickael
影响因子：
3.7
作者：
Archin NM;Cheema M;Parker D;Wiegand A;Bosch RJ;Coffin JM;Eron J;Cohen M;Margolis DM
通讯作者：
Margolis DM
影响因子：
16
作者：
He N;Liu M;Hsu J;Xue Y;Chou S;Burlingame A;Krogan NJ;Alber T;Zhou Q
通讯作者：
Zhou Q
影响因子：
6.7
作者：
通讯作者：
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