Biophysical and structural study of La Crosse virus endonuclease inhibition for the development of new antiviral options

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ Pub Date : 2024-05-01 DOI:10.1107/S205225252400304X

Mikael Feracci , Sergio Hernandez , Laura Garlatti , Clemence Mondielli , Renaud Vincentelli , Bruno Canard , Juan Reguera , François Ferron , Karine Alvarez , Z.-J. Liu (Editor)

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Abstract

A structural analysis of several metal-ion binders that inhibit viral endonucleases is performed.

The large Bunyavirales order includes several families of viruses with a segmented ambisense (−) RNA genome and a cytoplasmic life cycle that starts by synthesizing viral mRNA. The initiation of transcription, which is common to all members, relies on an endonuclease activity that is responsible for cap-snatching. In La Crosse virus, an orthobunyavirus, it has previously been shown that the cap-snatching endonuclease resides in the N-terminal domain of the L protein. Orthobunyaviruses are transmitted by arthropods and cause diseases in cattle. However, California encephalitis virus, La Crosse virus and Jamestown Canyon virus are North American species that can cause encephalitis in humans. No vaccines or antiviral drugs are available. In this study, three known Influenza virus endonuclease inhibitors (DPBA, L-742,001 and baloxavir) were repurposed on the La Crosse virus endonuclease. Their inhibition was evaluated by fluorescence resonance energy transfer and their mode of binding was then assessed by differential scanning fluorimetry and microscale thermophoresis. Finally, two crystallographic structures were obtained in complex with L-742,001 and baloxavir, providing access to the structural determinants of inhibition and offering key information for the further development of Bunyavirales endonuclease inhibitors.

查看原文本刊更多论文

拉克罗斯病毒内切酶抑制的生物物理和结构研究，以开发新的抗病毒方案。

布尼亚病毒纲（Bunyavirales）包括几个病毒家族，其基因组为分段的反义（-）RNA，细胞质生命周期从合成病毒 mRNA 开始。转录的启动对所有成员来说都是共同的，它依赖于一种负责抓帽的内切酶活性。在拉克罗斯病毒（一种正圆病毒）中，先前的研究表明，抓帽内切酶位于 L 蛋白的 N 端结构域。正圆病毒通过节肢动物传播，并导致牛生病。不过，加利福尼亚脑炎病毒、拉克罗斯病毒和詹姆斯敦峡谷病毒属于北美物种，可导致人类脑炎。目前还没有疫苗或抗病毒药物。在这项研究中，三种已知的流感病毒内切酶抑制剂（DPBA、L-742,001 和巴洛沙韦）被重新用于拉克罗斯病毒内切酶。通过荧光共振能量转移评估了它们的抑制作用，然后通过差示扫描荧光测定法和微尺度热泳评估了它们的结合模式。最后，获得了两种晶体结构与 L-742,001 和巴洛沙韦的复合物，从而了解了抑制作用的结构决定因素，为进一步开发布尼亚病毒内切酶抑制剂提供了关键信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

IUCrJ CHEMISTRY, MULTIDISCIPLINARYCRYSTALLOGRAPH-CRYSTALLOGRAPHY

CiteScore

7.50

自引率

5.10%

发文量

审稿时长

10 weeks

期刊介绍： IUCrJ is a new fully open-access peer-reviewed journal from the International Union of Crystallography (IUCr). The journal will publish high-profile articles on all aspects of the sciences and technologies supported by the IUCr via its commissions, including emerging fields where structural results underpin the science reported in the article. Our aim is to make IUCrJ the natural home for high-quality structural science results. Chemists, biologists, physicists and material scientists will be actively encouraged to report their structural studies in IUCrJ.