一种对登革病毒具有显著活性的杂环分子。
A heterocyclic molecule with significant activity against dengue virus.
作者信息
Nair Vasu, Chi Guochen, Shu Qingning, Julander Justin, Smee Donald F
机构信息
Department of Pharmaceutical and Biomedical Sciences and the Center for Drug Discovery, University of Georgia, Athens, GA 30602, USA.
出版信息
Bioorg Med Chem Lett. 2009 Mar 1;19(5):1425-7. doi: 10.1016/j.bmcl.2009.01.031. Epub 2009 Jan 15.
Abstract
There are no specific approved drugs or vaccines for the treatment or prevention of infectious dengue virus and there are very few compounds known that inhibit the replication of this virus. This letter describes the concise synthesis of two uracil-based multifunctional compounds. One of these compounds (1) has strong activity against dengue virus. It also exhibits low activity against a few other RNA viruses, but is highly active against yellow fever virus, a related flavivirus. It is likely that the mechanism of action of the antiviral activity of this compound is through its inhibition of the enzyme, inosine monophosphate dehydrogenase (IMPDH). Molecular modeling studies reveal that the compound can have specific hydrogen bonding interactions with a number of amino acids in the active site of IMPDH, a stacking interaction with the bound natural substrate, IMP, and the ability to interfere with the binding of NAD(+) with IMPDH, prior to the hydration step.
摘要
目前尚无专门批准用于治疗或预防登革热病毒感染的药物或疫苗，并且已知能够抑制该病毒复制的化合物非常少。本文描述了两种基于尿嘧啶的多功能化合物的简洁合成方法。其中一种化合物（1）对登革热病毒具有很强的活性。它对其他几种RNA病毒也表现出低活性，但对黄热病毒（一种相关的黄病毒）具有高活性。该化合物抗病毒活性的作用机制可能是通过抑制肌苷单磷酸脱氢酶（IMPDH）。分子模拟研究表明，该化合物能够与IMPDH活性位点中的多个氨基酸发生特异性氢键相互作用，与结合的天然底物IMP发生堆积相互作用，并能够在水合步骤之前干扰NAD(+)与IMPDH的结合。
相似文献
1
A heterocyclic molecule with significant activity against dengue virus.一种对登革病毒具有显著活性的杂环分子。
Bioorg Med Chem Lett. 2009 Mar 1;19(5):1425-7. doi: 10.1016/j.bmcl.2009.01.031. Epub 2009 Jan 15.
2
A novel benzo-heterocyclic amine derivative N30 inhibits influenza virus replication by depression of Inosine-5'-Monophospate Dehydrogenase activity.一种新型苯并杂环胺衍生物N30通过抑制肌苷-5'-单磷酸脱氢酶活性来抑制流感病毒复制。
Virol J. 2017 Mar 15;14(1):55. doi: 10.1186/s12985-017-0724-6.
3
Inosine monophosphate dehydrogenase as a probe in antiviral drug discovery.肌苷单磷酸脱氢酶作为抗病毒药物研发的探针。
Antivir Chem Chemother. 2007;18(5):245-58. doi: 10.1177/095632020701800501.
4
Crystal structure at 2.4 A resolution of Borrelia burgdorferi inosine 5'-monophosphate dehydrogenase: evidence of a substrate-induced hinged-lid motion by loop 6.分辨率为2.4埃的伯氏疏螺旋体肌苷5'-单磷酸脱氢酶晶体结构：6号环底物诱导的铰链盖运动的证据。
Biochemistry. 2000 Apr 18;39(15):4533-42. doi: 10.1021/bi992645l.
5
Inactivation of inosine 5'-monophosphate dehydrogenase by the antiviral agent 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide 5'-monophosphate.抗病毒药物5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺5'-单磷酸酯对肌苷5'-单磷酸脱氢酶的失活作用
Biochemistry. 1996 Jan 9;35(1):95-101. doi: 10.1021/bi951499q.
6
Bacillus anthracis inosine 5'-monophosphate dehydrogenase in action: the first bacterial series of structures of phosphate ion-, substrate-, and product-bound complexes.炭疽芽孢杆菌肌苷 5′-单磷酸脱氢酶的作用机制：首个结合磷酸盐离子、底物和产物的系列细菌结构复合物。
Biochemistry. 2012 Aug 7;51(31):6148-63. doi: 10.1021/bi300511w. Epub 2012 Jul 25.
7
Characterization of the mode of action of a potent dengue virus capsid inhibitor.鉴定强效登革热病毒衣壳抑制剂的作用模式。
J Virol. 2014 Oct;88(19):11540-55. doi: 10.1128/JVI.01745-14. Epub 2014 Jul 23.
8
IMPDH as a biological probe for RNA antiviral drug discovery: synthesis, enzymology, molecular docking, and antiviral activity of new ribonucleosides with surrogate bases.肌苷-5'-单磷酸脱氢酶作为RNA抗病毒药物发现的生物探针：具有替代碱基的新型核糖核苷的合成、酶学、分子对接及抗病毒活性
Nucleosides Nucleotides Nucleic Acids. 2007;26(6-7):651-4. doi: 10.1080/15257770701490506.
9
Acid-base catalysis in the chemical mechanism of inosine monophosphate dehydrogenase.肌苷单磷酸脱氢酶化学机制中的酸碱催化作用。
Biochemistry. 1999 Apr 6;38(14):4433-40. doi: 10.1021/bi9829579.
10
The structure of inosine 5'-monophosphate dehydrogenase and the design of novel inhibitors.肌苷5'-单磷酸脱氢酶的结构与新型抑制剂的设计。
Immunopharmacology. 2000 May;47(2-3):163-84. doi: 10.1016/s0162-3109(00)00193-4.
引用本文的文献
1
Sulfonic acid grafted on silica-shell silver nanoparticles as a novel catalyst for the preparation of pyrimido[4,5-]quinolines.接枝在二氧化硅壳银纳米颗粒上的磺酸作为制备嘧啶并[4,5 - ]喹啉的新型催化剂。
Nanoscale Adv. 2025 Jul 7;7(17):5221-5237. doi: 10.1039/d5na00393h. eCollection 2025 Aug 19.
2
Multicomponent synthesis of pyrimido[4,5-b] quinolines over a carbocationic catalytic system.在碳正离子催化体系上嘧啶并[4,5-b]喹啉的多组分合成
Sci Rep. 2023 Oct 1;13(1):16501. doi: 10.1038/s41598-023-43793-5.
3
Nano-[FeO@SiO/-propyl-1-(thiophen-2-yl)ethanimine][ZnCl] as a nano magnetite Schiff base complex and heterogeneous catalyst for the synthesis of pyrimido[4,5-]quinolones.纳米-[FeO@SiO/-丙基-1-(噻吩-2-基)乙亚胺][ZnCl]作为一种纳米磁铁矿席夫碱配合物及用于合成嘧啶并[4,5-]喹啉酮的多相催化剂。
RSC Adv. 2022 Feb 14;12(9):5386-5394. doi: 10.1039/d2ra00213b. eCollection 2022 Feb 10.
4
Progress in Anti-Mammarenavirus Drug Development.抗马动脉炎病毒药物研发进展。
Viruses. 2021 Jun 22;13(7):1187. doi: 10.3390/v13071187.
5
A novel benzo-heterocyclic amine derivative N30 inhibits influenza virus replication by depression of Inosine-5'-Monophospate Dehydrogenase activity.一种新型苯并杂环胺衍生物N30通过抑制肌苷-5'-单磷酸脱氢酶活性来抑制流感病毒复制。
Virol J. 2017 Mar 15;14(1):55. doi: 10.1186/s12985-017-0724-6.
6
Antiviral activity of an N-allyl acridone against dengue virus.一种N-烯丙基吖啶酮对登革病毒的抗病毒活性。
J Biomed Sci. 2015 Apr 17;22(1):29. doi: 10.1186/s12929-015-0134-2.
7
Synthesis of a novel carbocyclic analog of bredinin.合成布雷迪宁的新型碳环类似物。
Molecules. 2013 Sep 17;18(9):11576-85. doi: 10.3390/molecules180911576.
8
Understanding the dengue viruses and progress towards their control.了解登革热病毒及其控制进展。
Biomed Res Int. 2013;2013:690835. doi: 10.1155/2013/690835. Epub 2013 Jul 9.
9
Experimental therapies for yellow fever.黄热病的实验疗法。
Antiviral Res. 2013 Feb;97(2):169-79. doi: 10.1016/j.antiviral.2012.12.002. Epub 2012 Dec 10.
10
Structure and functionality in flavivirus NS-proteins: perspectives for drug design.黄病毒NS蛋白的结构与功能：药物设计的前景
Antiviral Res. 2010 Aug;87(2):125-48. doi: 10.1016/j.antiviral.2009.11.009. Epub 2009 Nov 27.
本文引用的文献
1
Inosine monophosphate dehydrogenase as a probe in antiviral drug discovery.肌苷单磷酸脱氢酶作为抗病毒药物研发的探针。
Antivir Chem Chemother. 2007;18(5):245-58. doi: 10.1177/095632020701800501.
2
Progress for dengue virus diseases. Towards the NS2B-NS3pro inhibition for a therapeutic-based approach.登革病毒疾病的进展。迈向基于治疗方法的NS2B-NS3蛋白酶抑制。
FEBS J. 2007 Jun;274(12):2986-3002. doi: 10.1111/j.1742-4658.2007.05831.x. Epub 2007 May 17.
3
Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery.肌苷单磷酸脱氢酶（IMPDH）作为药物研发的靶点。
Med Res Rev. 2008 Mar;28(2):219-32. doi: 10.1002/med.20104.
4
c-Src protein kinase inhibitors block assembly and maturation of dengue virus.c-Src蛋白激酶抑制剂可阻断登革病毒的组装和成熟。
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3520-5. doi: 10.1073/pnas.0611681104. Epub 2007 Feb 21.
5
Dengue virus RNA polymerase NS5: a potential therapeutic target?
Curr Drug Targets. 2006 Dec;7(12):1623-38. doi: 10.2174/138945006779025383.
6
Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis.登革病毒复制和发病机制的病毒及宿主决定因素解析的最新进展。
J Virol. 2006 Dec;80(23):11418-31. doi: 10.1128/JVI.01257-06. Epub 2006 Aug 23.
7
Dengue prevention and 35 years of vector control in Singapore.新加坡的登革热预防与35年病媒控制
Emerg Infect Dis. 2006 Jun;12(6):887-93. doi: 10.3201/10.3201/eid1206.051210.
8
Inhibitors of inosine monophosphate dehydrogenase: probes for antiviral drug discovery.肌苷单磷酸脱氢酶抑制剂：抗病毒药物研发的探针
Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):717-20. doi: 10.1081/ncn-200060308.
9
The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase.利巴韦林在体外对黄病毒和副粘病毒发挥抗病毒活性的主要机制是通过抑制肌苷酸脱氢酶介导的。
J Virol. 2005 Feb;79(3):1943-7. doi: 10.1128/JVI.79.3.1943-1947.2005.
10
Dengue epidemiology: virus epidemiology, ecology, and emergence.登革热流行病学：病毒流行病学、生态学与新出现情况。
Adv Virus Res. 2003;61:235-89. doi: 10.1016/s0065-3527(03)61006-7.
Zotero 插件