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Synthesis of 4H-Pyrazolo[3,4-d]pyrimidin-4-one Hydrazine Derivatives as a Potential Inhibitor for the Self-Assembly of TMV Particles
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-01-19 , DOI: 10.1021/acs.jafc.3c05334 Ya Wang 1 , Shengxin Guo 1 , Wei Sun 1 , Hong Tu 1 , Yao Tang 1 , Ying Xu 1 , Renjiang Guo 1 , Zhichao Zhao 1 , Zhaokai Yang 1 , Jian Wu 1
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-01-19 , DOI: 10.1021/acs.jafc.3c05334 Ya Wang 1 , Shengxin Guo 1 , Wei Sun 1 , Hong Tu 1 , Yao Tang 1 , Ying Xu 1 , Renjiang Guo 1 , Zhichao Zhao 1 , Zhaokai Yang 1 , Jian Wu 1
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Tobacco mosaic virus coat protein (TMV-CP), as a potential target for the development of antiviral agents, can assist in the long-distance movement of viruses and plays an extremely important role in virus replication and propagation. This work focuses on the synthesis and the action mechanism of novel 4H-pyrazolo[3,4-d] pyrimidin-4-one hydrazine derivatives. The synthesized compounds exhibited promising antiviral activity on TMV. Specifically, compound G2 exhibited high inactivating activity (93%) toward TMV, slightly better than commercial reagent NNM (90%). The action of mechanism was further explored by employed molecular docking, molecular dynamics simulation, microscale thermophoresis, qRT-PCR, and transmission electron microscopy. Results indicated that G2 had the capability to interact with amino acid residues such as Trp352, Tyr139, and Asn73 in the active pocket of TMV-CP, creating strong hydrophobic interactions and thus obstructing the virus’s self-assembly.
中文翻译：
4H-吡唑并[3,4-d]嘧啶-4-酮肼衍生物的合成作为TMV颗粒自组装的潜在抑制剂
烟草花叶病毒外壳蛋白（TMV-CP）作为抗病毒药物开发的潜在靶点，可以协助病毒长距离移动，在病毒复制和传播中发挥着极其重要的作用。本工作重点研究新型4H-吡唑并[3,4- d ]嘧啶-4-酮肼衍生物的合成及其作用机制。合成的化合物对 TMV 表现出良好的抗病毒活性。具体而言，化合物G2对TMV表现出较高的灭活活性（93%），略好于商业试剂NNM（90%）。通过分子对接、分子动力学模拟、微尺度热泳、qRT-PCR、透射电镜等手段进一步探讨其作用机制。结果表明， G2能够与TMV-CP活性口袋中的Trp352 、 Tyr139和Asn73等氨基酸残基相互作用，产生强疏水相互作用，从而阻碍病毒的自组装。
更新日期：2024-01-19
中文翻译：
4H-吡唑并[3,4-d]嘧啶-4-酮肼衍生物的合成作为TMV颗粒自组装的潜在抑制剂
烟草花叶病毒外壳蛋白（TMV-CP）作为抗病毒药物开发的潜在靶点，可以协助病毒长距离移动，在病毒复制和传播中发挥着极其重要的作用。本工作重点研究新型4H-吡唑并[3,4- d ]嘧啶-4-酮肼衍生物的合成及其作用机制。合成的化合物对 TMV 表现出良好的抗病毒活性。具体而言，化合物G2对TMV表现出较高的灭活活性（93%），略好于商业试剂NNM（90%）。通过分子对接、分子动力学模拟、微尺度热泳、qRT-PCR、透射电镜等手段进一步探讨其作用机制。结果表明， G2能够与TMV-CP活性口袋中的Trp352 、 Tyr139和Asn73等氨基酸残基相互作用，产生强疏水相互作用，从而阻碍病毒的自组装。
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