Evaluation of EED Inhibitors as a Class of PRC2-Targeted Small Molecules for HIV Latency Reversal.,ACS Infectious Diseases

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Evaluation of EED Inhibitors as a Class of PRC2-Targeted Small Molecules for HIV Latency Reversal.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-04-29 , DOI: 10.1021/acsinfecdis.9b00514
Anne-Marie W Turner _{1,

2} , Raghuvar Dronamraju ₃ , Frances Potjewyd ₄ , Katherine S James ₁ , Daniel K Winecoff ₁ , Jennifer L Kirchherr ₁ , Nancie M Archin _{1,

2} , Edward P Browne _{1,

2} , Brian D Strahl ₃ , David M Margolis _{1,

2,

5,

6} , Lindsey I James _{1,

4}

Affiliation

A hallmark of human immunodeficiency type-1 (HIV) infection is the integration of the viral genome into host chromatin, resulting in a latent reservoir that persists despite antiviral therapy or immune response. Thus, key priorities toward eradication of HIV infection are to understand the mechanisms that allow HIV latency and to develop latency reversal agents (LRAs) that can facilitate the clearance of latently infected cells. The repressive H3K27me3 histone mark, catalyzed by the PRC2 complex, plays a pivotal role in transcriptional repression at the viral promoter in both cell line and primary CD4+ T cell models of latency. EZH2 inhibitors which block H3K27 methylation have been shown to act as LRAs, suggesting other PRC2 components could also be potential targets for latency reversal. EED, a core component of PRC2, ensures the propagation of H3K27me3 by allosterically activating EZH2 methyltransferase activity. Therefore, we sought to investigate if inhibition of EED would also reverse latency. Inhibitors of EED, EED226 and A-395, demonstrated latency reversal activity as single agents, and this activity was further enhanced when used in combination with other known LRAs. Loss of H3K27me3 following EED inhibition significantly increased the levels of H3K27 acetylation globally and at the HIV LTR. These results further confirm that PRC2 mediated repression plays a significant role in the maintenance of HIV latency and suggest that EED may serve as a promising new target for LRA development.

中文翻译：

EED 抑制剂作为一类用于 HIV 潜伏期逆转的 PRC2 靶向小分子的评估。

人类免疫缺陷 1 型 (HIV) 感染的一个标志是病毒基因组整合到宿主染色质中，导致尽管抗病毒治疗或免疫反应仍然存在的潜在储库。因此，根除 HIV 感染的关键优先事项是了解允许 HIV 潜伏的机制，并开发可促进潜伏感染细胞清除的潜伏期逆转剂 (LRA)。由 PRC2 复合物催化的抑制性 H3K27me3 组蛋白标记在细胞系和原代 CD4+ T 细胞潜伏模型中的病毒启动子转录抑制中起着关键作用。阻断 H3K27 甲基化的 EZH2 抑制剂已被证明可充当 LRA，这表明其他 PRC2 成分也可能是潜伏期逆转的潜在目标。EED，PRC2的核心组成部分，通过变构激活 EZH2 甲基转移酶活性确保 H3K27me3 的繁殖。因此，我们试图调查抑制 EED 是否也会逆转潜伏期。EED、EED226 和 A-395 的抑制剂作为单一药物表现出潜伏期逆转活性，当与其他已知的 LRA 联合使用时，这种活性会进一步增强。EED 抑制后 H3K27me3 的丢失显着增加了全球和 HIV LTR 的 H3K27 乙酰化水平。这些结果进一步证实 PRC2 介导的抑制在维持 HIV 潜伏期中起着重要作用，并表明 EED 可能成为 LRA 发展的一个有前途的新目标。EED、EED226 和 A-395 的抑制剂作为单一药物表现出潜伏期逆转活性，当与其他已知的 LRA 联合使用时，这种活性会进一步增强。EED 抑制后 H3K27me3 的丢失显着增加了全球和 HIV LTR 的 H3K27 乙酰化水平。这些结果进一步证实 PRC2 介导的抑制在维持 HIV 潜伏期中起着重要作用，并表明 EED 可能成为 LRA 发展的一个有前途的新目标。EED、EED226 和 A-395 的抑制剂作为单一药物表现出潜伏期逆转活性，当与其他已知的 LRA 联合使用时，这种活性会进一步增强。EED 抑制后 H3K27me3 的丢失显着增加了全球和 HIV LTR 的 H3K27 乙酰化水平。这些结果进一步证实 PRC2 介导的抑制在维持 HIV 潜伏期中起着重要作用，并表明 EED 可能成为 LRA 发展的一个有前途的新目标。

更新日期：2020-04-29

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