Targeting of CDK9 with indirubin 3'-monoxime safely and durably reduces HIV viremia in chronically infected humanized mice.
Targeting of CDK9 with indirubin 3'-monoxime safely and durably reduces HIV viremia in chronically infected humanized mice.
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DOI：
10.1371/journal.pone.0183425
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Heredia A
中科院分区：
文献类型：
--
作者：
Medina-Moreno S;Dowling TC;Zapata JC;Le NM;Sausville E;Bryant J;Redfield RR;Heredia A
HIV在人类宿主中的成功繁殖需要进入允许细胞、病毒RNA的逆转录、整合到人类基因组中、整合的前病毒的转录以及新病毒颗粒的组装/释放。目前，除了前病毒转录外，存在针对这些病毒步骤中的每一个的抗逆转录病毒药物。HIV转录抑制剂既可以增加治疗效力，又可以抑制耐药菌株。细胞周期蛋白依赖性激酶9（CDK 9）作为HIV达特蛋白的辅因子，并且是前病毒有效转录所需的。先前的研究已经表明，CDK 9抑制剂靛玉红3 '-单肟（IM）在体外和人源化小鼠（PBMC-NSG模型）中HIV急性感染的短期体内研究中抑制HIV转录，这表明了治疗潜力。本研究的目的是评价IM在人源化小鼠（HSC-NSG模型）慢性HIV感染期间的毒性、药代动力学和长期抗病毒活性。我们表明，IM浓度高于EC 50值迅速达到，并在血浆中持续> 3小时，无毒浓度持久降低HIV RNA水平。此外，在体外感染性试验中，IM增强了逆转录酶、蛋白酶和整合酶抑制剂类抗逆转录病毒药物的抗病毒活性。总之，IM可以增强目前的抗逆转录病毒治疗，并可以通过阻止前病毒的表达来帮助实现HIV患者的“功能性治愈”。
Successful propagation of HIV in the human host requires entry into a permissive cell, reverse transcription of viral RNA, integration into the human genome, transcription of the integrated provirus, and assembly/release of new virus particles. Currently, there are antiretrovirals against each of these viral steps, except for provirus transcription. An inhibitor of HIV transcription could both increase potency of treatment and suppress drug-resistant strains. Cellular cyclin-dependent kinase 9 (CDK9) serves as a cofactor for the HIV Tat protein and is required for effective transcription of the provirus. Previous studies have shown that the CDK9 inhibitor Indirubin 3’-monoxime (IM) inhibits HIV transcription in vitro and in short-term in vivo studies of HIV acute infection in humanized mice (PBMC-NSG model), suggesting a therapeutic potential. The objective of this study is to evaluate the toxicity, pharmacokinetics and long-term antiviral activity of IM during chronic HIV infection in humanized mice (HSC-NSG model). We show that IM concentrations above EC50 values are rapidly achieved and sustained for > 3 h in plasma, and that non-toxic concentrations durably reduce HIV RNA levels. In addition, IM enhanced the antiviral activity of antiretrovirals from the reverse transcriptase, protease and integrase inhibitor classes in in vitro infectivity assays. In summary, IM may enhance current antiretroviral treatments and could help achieve a “functional cure” in HIV patients by preventing expression of proviruses.
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EFC6663的最终结果：一项多中心，国际，第2阶段研究的Alvocidib研究，针对氟达拉滨 - 难治性慢性淋巴细胞性白血病患者。
影响因子：
2.7
作者：
Lanasa MC;Andritsos L;Brown JR;Gabrilove J;Caligaris-Cappio F;Ghia P;Larson RA;Kipps TJ;Leblond V;Milligan DW;Janssens A;Johnson AJ;Heerema NA;Bühler A;Stilgenbauer S;Devin J;Hallek M;Byrd JC;Grever MR
通讯作者：
Grever MR
黄叶替醇在复发多发性骨髓瘤中进行的I期试验。
影响因子：
3
作者：
Hofmeister, Craig C.;Poi, Ming;Bowers, Mindy A.;Zhao, Weiqiang;Phelps, Mitch A.;Benson, Don M.;Kraut, Eric H.;Farag, Sherif;Efebera, Yvonne A.;Sexton, Jennifer;Lin, Thomas S.;Grever, Michael;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
6.1
作者：
Ding, Yun;Qiao, Aimin;Fan, Guo-Huang
通讯作者：
Fan, Guo-Huang
影响因子：
20.3
作者：
Byrd, John C.;Lin, Thomas S.;Grever, Michael R.
通讯作者：
Grever, Michael R.
DOI：
10.1073/pnas.1511144112
发表时间：
2015-07-28
影响因子：
11.1
作者：
Heredia, Alonso;Le, Nhut;Redfield, Robert R.
通讯作者：
Redfield, Robert R.