N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry,RSC Medicinal Chemistry

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N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-10-19 00:00:00 , DOI: 10.1039/c7md00424a
A. A. Kononova _{1,

2,

3} , A. S. Sokolova _{1,

2,

3,

4,

5} , S. V. Cheresiz _{1,

2,

3,

6,

7} , O. I. Yarovaya _{1,

2,

3,

4,

5} , R. A. Nikitina _{3,

7,

8,

9,

10} , A. A. Chepurnov _{3,

7,

8,

9,

10} , A. G. Pokrovsky _{1,

2,

3} , N. F. Salakhutdinov _{1,

2,

3,

4,

5}

Affiliation

There is currently no approved antiviral therapy for treatment of Marburg virus disease (MVD). Although filovirus infection outbreaks are quite rare, the high mortality rates in such outbreaks make the development of anti-filoviral drugs an important goal of medical chemistry and virology. Here, we performed screening of a large library of natural derivatives for their virus entry inhibition activity using pseudotype systems. The bornyl ester derivatives containing saturated N-heterocycles exhibited the highest antiviral activity. It is supposed that compounds with specific inhibitory activity toward MarV-GP-dependent virus entry will inhibit the rVSIV-ΔG-MarV-GP pseudotype much more efficiently than the control rVSIV-ΔG-G pseudotype. At the same time, the compounds similarly inhibiting both pseudotypes will likely affect rVSIV capsid replication or the cellular mechanisms common to the entry of both viruses. Borneol itself is not active against both pseudotypes and is nontoxic, whereas its derivatives have varying toxicity and antiviral activity. Among low-toxic borneol derivatives, six compounds turned out to be relatively specific inhibitors of MarV-GP-mediated infection (SC > 10). Of them, compound 6 containing a methylpiperidine moiety exhibited the highest virus-specific activity. Notably, the virus-specific activity of this compound is twice as high as that of the reference.

中文翻译：

N-杂环冰片衍生物作为马尔堡病毒糖蛋白介导的VSIV假型进入的抑制剂

目前尚无批准的抗病毒疗法可用于治疗马尔堡病毒病（MVD）。尽管丝状病毒感染暴发非常罕见，但此类暴发中的高死亡率使抗丝病毒药物的开发成为医学化学和病毒学的重要目标。在这里，我们使用假型系统对大型天然衍生物的病毒进入抑制活性进行了筛选。含有饱和N-杂环的冰片酯衍生物表现出最高的抗病毒活性。认为对MarV-GP依赖性病毒进入具有特定抑制活性的化合物将比对照rVSIV-ΔG-G假型更有效地抑制rVSIV-ΔG-MarV-GP假型。同时，同样抑制两种假型的化合物可能会影响rVSIV衣壳的复制或两种病毒共同进入的细胞机制。冰片本身对两种假型均无活性，并且无毒，而其衍生物具有不同的毒性和抗病毒活性。在低毒性冰片衍生物中，有六种化合物被证明是MarV-GP介导的感染的相对特异性抑制剂（SC> 10）。其中，复合含有甲基哌啶部分的6显示出最高的病毒特异性活性。值得注意的是，该化合物的病毒特异性活性是参考化合物的两倍。

更新日期：2017-11-10

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