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Elimination of HIV-1 Latently Infected Cells by Gnidimacrin and a Selective HDAC Inhibitor
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2018-02-06 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00012
Li Huang,Wei-Hong Lai,Lei Zhu,Wei Li,Lei Wei,Kuo-Hsiung Lee,Lan Xie,Chin-Ho Chen

We have previously reported gnidimacrin (GM), a protein kinase C (PKC) agonist, significantly reduces the frequency of HIV-1 latently infected cells in peripheral blood mononuclear cells (PBMCs) from patients undergoing successful antiretroviral therapy at low picomolar concentrations ex vivo, which is distinct from other latency reversing agents. In this study, we demonstrate that strong viral reactivation by GM is a mechanism for elimination of latently infected cells, and a histone deacetylase inhibitor (HDACI), a thiophenyl benzamide (TPB), further potentiated the efficacy of GM against latent HIV-1. The effect of GM on latent HIV-1 activation was potentiated by TPB in cell models by 2–3-fold. The GM/TPB combination further decreased the frequency of HIV-infected cells in latently infected patient PBMCs over 3-fold when compared with GM alone, which caused a 5-fold reduction compared with the solvent control. Thus, GM/TPB is a unique combination that may reduce latent HIV-1 reservoirs at nontoxic concentrations.

中文翻译:

尼迪马林和选择性HDAC抑制剂消除HIV-1潜伏感染的细胞

我们以前曾报道gnidimacrin(GM),蛋白激酶C(PKC)激动剂,显著降低外周血单核细胞(PBMC)的HIV-1潜伏感染的细胞从在低皮摩尔浓度经历成功的抗逆转录病毒治疗的患者的频率离体,这与其他延迟反向代理不同。在这项研究中,我们证明了由GM进行的强大病毒再激活是消除潜伏感染细胞的机制,而组蛋白脱乙酰基酶抑制剂(HDACI),硫代苯甲酰胺(TPB)进一步增强了GM对潜在HIV-1的功效。TPB在细胞模型中将GM对潜在HIV-1激活的作用增强了2-3倍。与单独使用GM相比,GM / TPB组合进一步将潜伏感染患者PBMC中HIV感染细胞的频率降低了3倍以上,与溶剂对照组相比降低了5倍。因此,GM / TPB是一种独特的组合,可以减少无毒浓度的潜在HIV-1储库。
更新日期:2018-02-06
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