一种新型核苷类似物，对突变 sr39 单纯疱疹病毒-1（HSV-1）胸苷激酶（TK）具有强大的活性。
A new nucleoside analogue with potent activity against mutant sr39 herpes simplex virus-1 (HSV-1) thymidine kinase (TK).
机构信息
BRIGHT Institute, Molecular Imaging Center, Mallinckrodt Institute of Radiology, Department of Chemistry, Washington University School of Medicine , Box 8225, 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
出版信息
Org Lett. 2012 Jul 20;14(14):3568-71. doi: 10.1021/ol300728a. Epub 2012 Jul 5.
Abstract
Nucleoside analogues, such as penciclovir, ganciclovir, acyclovir, and their fluoro-substituted derivatives, have wide utility as antivirals. Among these analogues, FHBG ((18)F-Fluorohydroxybutylguanine) is a well-validated PET (positron emission tomography) probe for monitoring reporter gene expression. To evaluate whether or not imposing rigidity into the flexible side chain of FHBG 4 could also impact its interaction, with amino acid residues within the binding site of HSV1-TK (Herpes Simplex Virus-1 Thymidine Kinase), thus influencing its cytotoxic activity. Herein, the synthesis of a new fluorinated nucleoside analogue 6 (conceived via ligand-docking studies) is reported. Agent 6 demonstrates selective activity against HeLa cells stably transfected with mutant HSV1-sr39TK and is also 47-fold more potent than FHBG.
摘要
核苷类似物，如喷昔洛韦、更昔洛韦、阿昔洛韦及其氟取代衍生物，作为抗病毒药物有广泛的用途。在这些类似物中，FHBG（(18)F-氟羟丁基鸟嘌呤）是一种经过充分验证的 PET（正电子发射断层扫描）探针，可用于监测报告基因的表达。为了评估将 FHBG 4 的柔性侧链固定是否也会影响其与 HSV1-TK（单纯疱疹病毒 1 胸苷激酶）结合位点内氨基酸残基的相互作用，从而影响其细胞毒性活性。在此，报告了一种新的氟化核苷类似物 6 的合成（通过配体对接研究设想）。该试剂 6 对稳定转染突变型 HSV1-sr39TK 的 HeLa 细胞具有选择性活性，并且比 FHBG 强 47 倍。
相似文献
1
A new nucleoside analogue with potent activity against mutant sr39 herpes simplex virus-1 (HSV-1) thymidine kinase (TK).一种新型核苷类似物，对突变 sr39 单纯疱疹病毒-1（HSV-1）胸苷激酶（TK）具有强大的活性。
Org Lett. 2012 Jul 20;14(14):3568-71. doi: 10.1021/ol300728a. Epub 2012 Jul 5.
2
A new acycloguanosine-specific supermutant of herpes simplex virus type 1 thymidine kinase suitable for PET imaging and suicide gene therapy for potential use in patients treated with pyrimidine-based cytotoxic drugs.一种新型的单纯疱疹病毒1型胸苷激酶的无环鸟苷特异性超突变体，适用于正电子发射断层扫描（PET）成像和自杀基因治疗，可能用于接受嘧啶类细胞毒性药物治疗的患者。
J Nucl Med. 2008 May;49(5):713-20. doi: 10.2967/jnumed.107.046425. Epub 2008 Apr 15.
3
Molecular-genetic PET imaging using an HSV1-tk mutant reporter gene with enhanced specificity to acycloguanosine nucleoside analogs.使用对阿昔洛韦核苷类似物具有增强特异性的HSV1-tk突变报告基因进行分子遗传PET成像。
J Nucl Med. 2009 Mar;50(3):409-16. doi: 10.2967/jnumed.108.058735. Epub 2009 Feb 17.
4
CL1-SR39: A noninvasive molecular imaging model of prostate cancer suicide gene therapy using positron emission tomography.CL1-SR39：一种使用正电子发射断层扫描的前列腺癌自杀基因治疗的非侵入性分子成像模型。
J Urol. 2002 Sep;168(3):1193-8. doi: 10.1016/S0022-5347(05)64624-1.
5
PET imaging of HSV1-tk mutants with acquired specificity toward pyrimidine- and acycloguanosine-based radiotracers.对嘧啶和阿昔洛韦核苷类放射性示踪剂具有获得性特异性的单纯疱疹病毒1型胸苷激酶（HSV1-tk）突变体的正电子发射断层显像（PET）
Eur J Nucl Med Mol Imaging. 2009 Aug;36(8):1273-82. doi: 10.1007/s00259-009-1089-x. Epub 2009 Mar 4.
6
Testing the sensitivities of noncognate inhibitors to varicella zoster virus thymidine kinase: implications for postherpetic neuralgia therapy with existing agents.检测非同源抑制剂对水痘带状疱疹病毒胸苷激酶的敏感性：对现有药物治疗带状疱疹后神经痛的意义。
J Mol Model. 2014 Jul;20(7):2321. doi: 10.1007/s00894-014-2321-6. Epub 2014 Jun 25.
7
8
C-5 hydroxyethyl and hydroxypropyl acyclonucleosides as substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK): syntheses and biological evaluation.C-5 羟乙基和羟丙基环核苷作为单纯疱疹病毒 1 型胸苷激酶 (HSV-1 TK) 的底物：合成与生物学评价。
Molecules. 2013 May 2;18(5):5104-24. doi: 10.3390/molecules18055104.
9
Prediction of the binding mode of N2-phenylguanine derivative inhibitors to herpes simplex virus type 1 thymidine kinase.
J Comput Aided Mol Des. 1998 Jan;12(1):15-25. doi: 10.1023/a:1007930523818.
10
Synthesis and Characterization of 9-(4-[F]Fluoro-3-(hydroxymethyl)butyl)-2-(phenylthio)-6-oxopurine as a Novel PET Agent for Mutant Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Imaging.新型 PET 显像剂 9-(4-[F]氟-3-(羟甲基)丁基)-2-(苯硫基)-6-氧代嘌呤的合成与表征用于突变型单纯疱疹病毒 1 胸苷激酶报告基因显像。
Mol Imaging Biol. 2020 Oct;22(5):1151-1160. doi: 10.1007/s11307-020-01517-5.
引用本文的文献
1
Anti-viral activity of lysates against herpes simplex virus type-I infection: an and study.裂解物对单纯疱疹病毒I型感染的抗病毒活性：一项[具体内容缺失]研究。
Int J Ophthalmol. 2021 Oct 18;14(10):1463-1472. doi: 10.18240/ijo.2021.10.01. eCollection 2021.
2
Catalytic Enantioselective Addition of an Allyl Group to Ketones Containing a Tri-, a Di-, or a Monohalomethyl Moiety. Stereochemical Control Based on Distinctive Electronic and Steric Attributes of C-Cl, C-Br, and C-F Bonds.三卤代、二卤代或一卤代甲基酮的烯丙基化的催化对映选择性加成。基于 C-Cl、C-Br 和 C-F 键的独特电子和空间属性的立体化学控制。
J Am Chem Soc. 2019 Oct 9;141(40):16125-16138. doi: 10.1021/jacs.9b08443. Epub 2019 Sep 25.
3
Cytotoxic 1,3-Thiazole and 1,2,4-Thiadiazole Alkaloids from Penicillium oxalicum: Structural Elucidation and Total Synthesis.从草酸青霉中分离得到的细胞毒 1,3-噻唑和 1,2,4-噻二唑生物碱：结构阐明和全合成。
Molecules. 2016 Feb 26;21(3):232. doi: 10.3390/molecules21030232.
4
Silencing herpes simplex virus type 1 capsid protein encoding genes by siRNA: a promising antiviral therapeutic approach.通过小干扰RNA沉默单纯疱疹病毒1型衣壳蛋白编码基因：一种有前景的抗病毒治疗方法。
PLoS One. 2014 May 2;9(5):e96623. doi: 10.1371/journal.pone.0096623. eCollection 2014.
本文引用的文献
1
The role of topical 5% acyclovir and 1% hydrocortisone cream (Xerese™) in the treatment of recurrent herpes simplex labialis.局部应用 5%阿昔洛韦和 1%氢化可的松乳膏（Xerese™）治疗复发性唇疱疹的作用。
Postgrad Med. 2010 Sep;122(5):1-6. doi: 10.3810/pgm.2010.09.2216.
2
Evaluation of tear samples for Herpes Simplex Virus 1 (HSV) detection in suspected cases of viral keratitis using PCR assay and conventional laboratory diagnostic tools.采用 PCR 法和常规实验室诊断工具评估疑似病毒性角膜炎患者的泪液样本中单纯疱疹病毒 1（HSV）的检测。
Br J Ophthalmol. 2011 Mar;95(3):415-8. doi: 10.1136/bjo.2010.191049. Epub 2010 Sep 18.
3
Docking of molecules identified in bioactive medicinal plants extracts into the p50 NF-kappaB transcription factor: correlation with inhibition of NF-kappaB/DNA interactions and inhibitory effects on IL-8 gene expression.生物活性药用植物提取物中鉴定出的分子与p50核因子-κB转录因子的对接：与核因子-κB/DNA相互作用抑制及对白细胞介素-8基因表达的抑制作用的相关性
BMC Struct Biol. 2008 Sep 3;8:38. doi: 10.1186/1472-6807-8-38.
4
The neurotropic herpes viruses: herpes simplex and varicella-zoster.嗜神经疱疹病毒：单纯疱疹病毒和水痘-带状疱疹病毒。
Lancet Neurol. 2007 Nov;6(11):1015-28. doi: 10.1016/S1474-4422(07)70267-3.
5
Expression of multidrug resistance (MDR) proteins and in vitro drug resistance in acute leukemias.急性白血病中多药耐药（MDR）蛋白的表达及体外耐药性
Hematology. 2007 Feb;12(1):33-7. doi: 10.1080/10245330600940030.
6
Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 1: herpes simplex virus infections.孕期单纯疱疹病毒和水痘-带状疱疹病毒感染：预防、诊断及治疗的当前理念。第1部分：单纯疱疹病毒感染
Med Microbiol Immunol. 2007 Jun;196(2):89-94. doi: 10.1007/s00430-006-0031-0. Epub 2006 Dec 13.
7
Second-generation triple reporter for bioluminescence, micro-positron emission tomography, and fluorescence imaging.用于生物发光、微型正电子发射断层扫描和荧光成像的第二代三重报告基因。
Mol Imaging. 2006 Oct-Dec;5(4):465-74.
8
Hydrogen bonding interactions of covalently bonded fluorine atoms: from crystallographic data to a new angular function in the GRID force field.共价键合氟原子的氢键相互作用：从晶体学数据到GRID力场中的新角度函数
J Med Chem. 2004 Oct 7;47(21):5114-25. doi: 10.1021/jm0498349.
9
Direct comparison of radiolabeled probes FMAU, FHBG, and FHPG as PET imaging agents for HSV1-tk expression in a human breast cancer model.在人乳腺癌模型中，将放射性标记探针FMAU、FHBG和FHPG作为用于检测单纯疱疹病毒1型胸苷激酶（HSV1-tk）表达的正电子发射断层显像（PET）成像剂进行直接比较。
Mol Imaging. 2004 Apr;3(2):76-84. doi: 10.1162/15353500200403160.
10
Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition.氟取代可阻断细胞色素P450 3A4（CYP3A4）代谢依赖性抑制作用：鉴定出（S）-N-[1-（4-氟-3-吗啉-4-基苯基）乙基]-3-（4-氟苯基）丙烯酰胺为一种口服生物可利用的钾通道蛋白Q2（KCNQ2）开放剂，且无CYP3A4代谢依赖性抑制作用。
J Med Chem. 2003 Aug 28;46(18):3778-81. doi: 10.1021/jm034111v.
Zotero 插件