Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus.,ACS Chemical Biology

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Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-01-16 , DOI: 10.1021/acschembio.9b00845
Philine Kirsch _{1,

2,

3} , Valentin Jakob _{1,

2,

3} , Walid A M Elgaher ₁ , Christine Walt ₁ , Kevin Oberhausen ₁ , Thomas F Schulz _{3,

4} , Martin Empting _{1,

2,

3}

Affiliation

With the aim to develop novel antiviral agents against Kaposi's Sarcoma Herpesvirus (KSHV), we are targeting the latency-associated nuclear antigen (LANA). This protein plays an important role in viral genome maintenance during latent infection. LANA has the ability to tether the viral genome to the host nucleosomes and, thus, ensures latent persistence of the viral genome in the host cells. By inhibition of the LANA-DNA interaction, we seek to eliminate or reduce the load of the viral DNA in the host. To achieve this goal, we screened our in-house library using a dedicated fluorescence polarization (FP)-based competition assay, which allows for the quantification of LANA-DNA-interaction inhibition by small organic molecules. We successfully identified three different compound classes capable of disrupting this protein-nucleic acid interaction. We characterized these compounds by IC50 dose-response evaluation and confirmed the compound-LANA interaction using surface plasmon resonance (SPR) spectroscopy. Furthermore, two of the three hit scaffolds showed only marginal cytotoxicity in two human cell lines. Finally, we conducted STD-NMR competition experiments with our new hit compounds and a previously described fragment-sized inhibitor. Based on these results, future compound linking approaches could serve as a promising strategy for further optimization studies in order to generate highly potent KSHV inhibitors.

中文翻译：

发现新型潜伏期相关的核抗原抑制剂作为抗卡波西氏肉瘤相关疱疹病毒的抗病毒剂。

为了开发针对卡波济氏肉瘤疱疹病毒（KSHV）的新型抗病毒药，我们的目标是与潜伏期相关的核抗原（LANA）。该蛋白在潜伏感染期间在病毒基因组维持中起重要作用。LANA具有将病毒基因组与宿主核小体连接的能力，因此可确保病毒基因组在宿主细胞中的潜在持久性。通过抑制LANA-DNA相互作用，我们寻求消除或减少宿主中病毒DNA的负荷。为了实现此目标，我们使用基于专用荧光偏振（FP）的竞争测定法筛选了我们的内部文库，该测定法可定量分析有机小分子对LANA-DNA相互作用的抑制作用。我们成功地确定了三种能够破坏这种蛋白质-核酸相互作用的化合物。我们通过IC50剂量反应评估对这些化合物进行了表征，并使用表面等离子体共振（SPR）光谱确认了化合物与LANA的相互作用。此外，三个命中支架中的两个在两个人类细胞系中仅显示出边缘细胞毒性。最后，我们使用新的热门化合物和先前描述的片段大小的抑制剂进行了STD-NMR竞争实验。基于这些结果，未来的化合物连接方法可以作为进一步优化研究的有前途的策略，以产生高效的KSHV抑制剂。我们使用新的热门化合物和先前描述的片段大小抑制剂进行了STD-NMR竞争实验。基于这些结果，未来的化合物连接方法可以作为进一步优化研究的有前途的策略，以产生高效的KSHV抑制剂。我们使用新的热门化合物和先前描述的片段大小抑制剂进行了STD-NMR竞争实验。基于这些结果，未来的化合物连接方法可以作为进一步优化研究的有前途的策略，以产生高效的KSHV抑制剂。

更新日期：2020-01-26

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