药学学报, 2020, 55(4): 734-743
引用本文:
张涛, 周忠霞, 展鹏, 刘新泳. 抗痘病毒药物化学研究新进展[J]. 药学学报, 2020, 55(4): 734-743.
ZHANG Tao, ZHOU Zhong-xia, ZHAN Peng, LIU Xin-yong. New progress in medicinal chemistry of anti-poxvirus drugs research[J]. Acta Pharmaceutica Sinica, 2020, 55(4): 734-743.

抗痘病毒药物化学研究新进展
张涛, 周忠霞, 展鹏, 刘新泳
山东大学药学院药物化学研究所, 化学生物学教育部重点实验室, 山东 济南 250012
摘要:
痘病毒(poxvirus)是已知病毒粒子中最大且结构最复杂的病毒,其中对人类具有致病性的主要为正痘病毒属(Orthopoxvirus)。近年来随着对正痘病毒生物结构和复制周期的深入了解,逐渐发现了一些高效低毒的新型小分子抑制剂,有些已进入临床试验阶段。本文对不同靶点的痘病毒抑制剂的研究进展进行了概述。
关键词:    痘病毒      正痘病毒      抑制剂      靶点      药物设计     
New progress in medicinal chemistry of anti-poxvirus drugs research
ZHANG Tao, ZHOU Zhong-xia, ZHAN Peng, LIU Xin-yong
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology(Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
Abstract:
Poxvirus is the largest and most complex virus of the known virions, and the main pathogenicity to humans is Orthopoxvirus. In recent years, with the deep understanding of the biological structure and replication cycle of Orthopoxvirus, new small molecular compounds with high efficiency and low toxicity have been discovered as new drugs, and some have entered the clinical trial stage. This article summarizes the research progress of poxvirus inhibitors with different targets.
Key words:    poxvirus    Orthopoxvirus    inhibitor    target    drug design   
收稿日期: 2019-11-26
DOI: 10.16438/j.0513-4870.2019-0954
基金项目: 国家自然科学基金重点国际合作研究项目(81420108027);山东省重点研发计划(2017CXGC1401,2019JZZY021011).
通讯作者: 刘新泳,Tel:86-531-88380270,E-mail:xinyongl@sdu.edu.cn;展鹏,E-mail:zhanpeng1982@sdu.edu.cn
Email: xinyongl@sdu.edu.cn;zhanpeng1982@sdu.edu.cn
相关功能
PDF(745KB) Free
打印本文
0
作者相关文章
张涛  在本刊中的所有文章
周忠霞  在本刊中的所有文章
展鹏  在本刊中的所有文章
刘新泳  在本刊中的所有文章

参考文献:
[1] Essbauer S, Pfeffer M, Meyer H. Zoonotic poxviruses[J]. Vet Microbiol, 2010, 140:229-236.
[2] Voigt EA, Kennedy RB, Poland GA. Defending against smallpox:a focus on vaccines[J]. Expert Rev Vaccines, 2016, 15:1197-1211.
[3] Kupferschmidt K. Labmade smallpox is possible, study shows[J]. Science, 2017, 357:115-116.
[4] Jing ZZ, Jia HJ, Zhou T. Poxvirus disease:a kind of zoonoses worthy of high attention[J]. Chin J Viral Dis (中国病毒病杂志), 2011, 1:416-418.
[5] Gunther T, Haas L, Alawi M, et al. Recovery of the first full-length genome sequence of a parapoxvirus directly from a clinical sample[J]. Sci Rep, 2017, 7:3734.
[6] Roberts KL, Smith GL. Vaccinia virus morphogenesis and dissemination[J]. Trends Microbiol, 2008, 16:472-479.
[7] Julien O, Beadle J R, Magee W C, et al. Solution structure of a DNA duplex containing the potent anti-poxvirus agent cidofovir[J]. J Am Chem Soc, 2011, 133:2264-2274.
[8] De Clercq E, Holy A. Acyclic nucleoside phosphonates:a key class of antiviral drugs[J]. Nat Rev Drug Discov, 2005, 4:928-940.
[9] Hoy SM. Tecovirimat:first global approval[J]. Drugs, 2018, 78:1377-1382.
[10] Duraffour S, Lorenzo MM, Zoller G, et al. ST-246 is a key antiviral to inhibit the viral F13L phospholipase, one of the essential proteins for orthopoxvirus wrapping[J]. J Antimicrob Chemother, 2015, 70:1367-1380.
[11] Carter GC, Law M, Hollinshead M, et al. Entry of the vaccinia virus intracellular mature virion and its interactions with glycosaminoglycans[J]. J Gen Virol, 2005, 86:1279-1290.
[12] Brown E, Senkevich TG, Moss B. Vaccinia virus F9 virion membrane protein is required for entry but not virus assembly, in contrast to the related L1 protein[J]. J Virol, 2006, 80:9455-9464.
[13] Ojeda S, Senkevich TG, Moss B. Entry of vaccinia virus and cell-cell fusion require a highly conserved cysteine-rich membrane protein encoded by the A16L gene[J]. J Virol, 2006, 80:51-61.
[14] Senkevich TG, Ojeda S, Townsley A, et al. Poxvirus multiprotein entry-fusion complex[J]. Proc Natl Acad Sci U S A, 2005, 102:18572-18577.
[15] Bell E, Shamim M, Whitbeck JC, et al. Antibodies against the extracellular enveloped virus B5R protein are mainly responsible for the EEV neutralizing capacity of vaccinia immune globulin[J]. Virology, 2004, 325:425-431.
[16] Demasi J, Du S, Lennon D, et al. Vaccinia virus telomeres:interaction with the viral I1, I6, and K4 proteins[J]. J Virol, 2001, 75:10090-10105.
[17] Boyle KA, Stanitsa ES, Greseth MD, et al. Evaluation of the role of the vaccinia virus uracil DNA glycosylase and A20 proteins as intrinsic components of the DNA polymerase holoenzyme[J]. J Biol Chem, 2011, 286:24702-24713.
[18] Prichard MN, Kern ER. Antiviral activity of 4'-thioIDU and thymidine analogs against orthopoxviruses[J]. Viruses, 2010, 2:1968-1983.
[19] Duraffour S, Drillien R, Andrei G, et al. KAY-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo[J]. Antimicrob Agents Chemother, 2014, 58:27-37.
[20] Magee WC, Hostetler KY, Evans DH. Mechanism of inhibition of vaccinia virus DNA polymerase by cidofovir diphosphate[J]. Antimicrob Agents Chemother, 2005, 49:3153-3162.
[21] Lanier R, Trost L, Tippin T, et al. Development of CMX001 for the treatment of poxvirus infections[J]. Viruses, 2010, 2:2740-2762.
[22] Tippin TK, Morrison ME, Brundage TM, et al. Brincidofovir is not a substrate for the human organic anion transporter 1:a mechanistic explanation for the lack of nephrotoxicity observed in clinical studies[J]. Ther Drug Monit, 2016, 38:777-786.
[23] Chittick G, Morrison M, Brundage T, et al. Short-term clinical safety profile of brincidofovir:a favorable benefit-risk proposition in the treatment of smallpox[J]. Antiviral Res, 2017, 143:269-277.
[24] Krecmerova M, Holy A, Andrei G, et al. Synthesis of ester prodrugs of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) as anti-poxvirus agents[J]. J Med Chem, 2010, 53:6825-6837.
[25] Zakharova VM, Serpi M, Krylov IS, et al. Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs:synthesis, stability, antiviral activity, and in vivo transport studies[J]. J Med Chem, 2011, 54:5680-5693.
[26] Ciustea M, Silverman JE, Druck Shudofsky AM, et al. Identification of non-nucleoside DNA synthesis inhibitors of vaccinia virus by high-throughput screening[J]. J Med Chem, 2008, 51:6563-6570.
[27] Nuth M, Guan H, Zhukovskaya N, et al. Design of potent poxvirus inhibitors of the heterodimeric processivity factor required for viral replication[J]. J Med Chem, 2013, 56:3235-3246.
[28] Nuth M, Huang L, Saw YL, et al. Identification of inhibitors that block vaccinia virus infection by targeting the DNA synthesis processivity factor D4[J]. J Med Chem, 2011, 54:3260-3267.
[29] Bougie I, Bisaillon M. The broad spectrum antiviral nucleoside ribavirin as a substrate for a viral RNA capping enzyme[J]. J Biol Chem, 2004, 279:22124-22130.
[30] Myskiw C, Piper J, Huzarewich R, et al. Nigericin is a potent inhibitor of the early stage of vaccinia virus replication[J]. Antiviral Res, 2010, 88:304-310.
[31] Quenelle DC, Keith KA, Kern ER. In vitro and in vivo evaluation of isatin-beta-thiosemicarbazone and marboran against vaccinia and cowpox virus infections[J]. Antiviral Res, 2006, 71:24-30.
[32] Cresawn SG, Condit RC. A targeted approach to identification of vaccinia virus postreplicative transcription elongation factors:genetic evidence for a role of the H5R gene in vaccinia transcription[J]. Virology, 2007, 363:333-341.
[33] Pirrung MC, Pansare SV, Sarma KD, et al. Combinatorial optimization of isatin-beta-thiosemicarbazones as anti-poxvirus agents[J]. J Med Chem, 2005, 48:3045-3050.
[34] Myskiw C, Deschambault Y, Jefferies K, et al. Aurintricarboxylic acid inhibits the early stage of vaccinia virus replication by targeting both cellular and viral factors[J]. J Virol, 2007, 81:3027-3032.
[35] Dower K, Filone CM, Hodges EN, et al. Identification of a pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library[J]. J Virol, 2012, 86:2632-2640.
[36] Maruri-Avidal L, Weisberg AS, Moss B. Direct formation of vaccinia virus membranes from the endoplasmic reticulum in the absence of the newly characterized L2-interacting protein A30.5[J]. J Virol, 2013, 87:12313-12326.
[37] Byrd CM,Hruby DE. Vaccinia virus proteolysis--a review[J]. Rev Med Virol, 2006, 16:187-202.
[38] Perdiguero B, Lorenzo MM, Blasco R. Vaccinia virus A34 glycoprotein determines the protein composition of the extracellular virus envelope[J]. J Virol, 2008, 82:2150-2160.
[39] Newsome TP, Scaplehorn N, Way M. SRC mediates a switch from microtubule-to actin-based motility of vaccinia virus[J]. Science, 2004, 306:124-129.
[40] Charity JC, Katz E, Moss B. Amino acid substitutions at multiple sites within the vaccinia virus D13 scaffold protein confer resistance to rifampicin[J]. Virology, 2007, 359:227-232.
[41] Garriga D, Headey S, Accurso C, et al. Structural basis for the inhibition of poxvirus assembly by the antibiotic rifampicin[J]. Proc Natl Acad Sci U S A. 2018, 115:8424-8429.
[42] Byrd CM, Bolken TC, Mjalli AM, et al. New class of orthopoxvirus antiviral drugs that block viral maturation[J]. J Virol, 2004, 78:12147-12156.
[43] Reeves PM, Bommarius B, Lebeis S, et al. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases[J]. Nat Med, 2005, 11:731-739.
[44] Pollara JJ, Laster SM, Petty IT. Inhibition of poxvirus growth by terameprocol, a methylated derivative of nordihydroguaiaretic acid[J]. Antiviral Res, 2010, 88:287-295.
[45] Bartlett N, Symons JA, Tscharke DC, et al. The vaccinia virus N1L protein is an intracellular homodimer that promotes virulence[J]. J Gen Virol, 2002, 83:1965-1976.
[46] Cheltsov AV, Aoyagi M, Aleshin A, et al. Vaccinia virus virulence factor N1L is a novel promising target for antiviral therapeutic intervention[J]. J Med Chem, 2010, 53:3899-3906.
[47] Mcguigan C, Hinsinger K, Farleigh L, et al. Novel antiviral activity of L-dideoxy bicyclic nucleoside analogues versus vaccinia and measles viruses in vitro[J]. J Med Chem, 2013, 56:1311-1322.
[48] Kang D, Zhang H, Zhou Z, et al. First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific anti-vaccinia and adenovirus agents via ‘privileged scaffold’ refining approach[J]. Bioorg Med Chem Lett, 2016, 26:5182-5186.
相关文献:
1.李敬, 姜向毅, 徐淑静, 崔清华, 杜瑞坤, 康东伟, 展鹏, 荣立军, 刘新泳.冠状病毒抑制剂研究的药物化学策略[J]. 药学学报, 2020,55(4): 537-553
2.马悦, 魏粉菊, 俞霁, 贾海永, 刘新泳, 展鹏.基于新靶标的HBV抑制剂研究进展(1):衣壳蛋白抑制剂[J]. 药学学报, 2020,55(4): 554-565
3.魏粉菊, 马悦, 俞霁, 贾海永, 刘新泳, 展鹏.基于新靶标的HBV抑制剂研究进展(2):RNase H及其他靶标[J]. 药学学报, 2020,55(4): 566-574
4.徐淑静, 刘新泳, 展鹏.呼吸道合胞病毒抑制剂研究新进展[J]. 药学学报, 2020,55(4): 597-610
5.修思雨, 张健, 鞠翰, 贾瑞芳, 黄兵, 展鹏, 刘新泳.抗流感病毒药物靶标及其小分子抑制剂的研究进展[J]. 药学学报, 2020,55(4): 611-626
6.李卓, 贾瑞芳, 展鹏, 刘新泳.寨卡病毒抑制剂研究新进展[J]. 药学学报, 2020,55(4): 627-639
7.宋淑, 高萍, 展鹏, 刘新泳.丙型肝炎病毒抑制剂研究进展[J]. 药学学报, 2020,55(4): 652-668
8.孙彦莹, 左晓芳, 展鹏, 刘新泳.抗腺病毒药物化学研究新进展[J]. 药学学报, 2020,55(4): 720-733
9.陶昱岑, 郝霞, 刘新泳, 展鹏.抗肠病毒71型药物化学新进展[J]. 药学学报, 2020,55(4): 744-753
10.梁瑞鹏, 赵彤, 展鹏, 刘新泳.西尼罗病毒抑制剂研究进展[J]. 药学学报, 2020,55(4): 763-772
11.康家雄, 朱江, 李爱秀, 靳玉瑞.化学合成类HIV整合酶和核糖核酸酶H双靶点抑制剂的研究进展[J]. 药学学报, 2019,54(8): 1392-1401
12.周忠霞, 孙林, 康东伟, 陈子慧, 唐苗苗, 李思雨, 展鹏, 刘新泳.具有新作用机制的HIV-1逆转录酶抑制剂研究进展[J]. 药学学报, 2018,53(5): 691-700
13.周俊廷, 蒋学阳, 冯锋, 孙昊鹏.多靶点药物设计策略及其研究进展[J]. 药学学报, 2018,53(12): 2012-2025
14.霍志鹏, 左晓芳, 康东伟, 展鹏, 刘新泳.抗艾滋病药物新靶标及其小分子抑制剂的研究进展[J]. 药学学报, 2018,53(3): 356-374
15.贾海永, 俞霁, 刘昕浩, 张健, 展鹏, 刘新泳.HIV-1核壳体蛋白NCp7抑制剂研究新进展[J]. 药学学报, 2017,52(11): 1652-1659
16.张友文, 张丹, 孙华.次黄嘌呤脱氢酶的基本功能及作为药物靶点的应用[J]. 药学学报, 2014,49(3): 285-292
17.关鑫磊, 姜凤超, 王悦, 吴鹏飞, 王芳, 陈建国.基于药效团模型的乙酰胆碱酯酶、聚腺苷二磷酸核糖聚合酶-1双靶点分子设计研究[J]. 药学学报, 2014,49(6): 819-823
18.刘 鸿, 展 鹏, 刘新泳.HIV-1逆转录酶和整合酶双靶点抑制剂研究进展[J]. 药学学报, 2013,48(4): 466-476
19.马宇衡,徐波,崔景荣,杨振军,张亮仁,张礼和.三肽四氮唑类20S蛋白酶体抑制剂的设计、合成与活性研究[J]. 药学学报, 2012,47(4): 472-478
20.王 柳, 展 鹏, 刘新泳.结构优化策略在HIV非核苷类逆转录酶抑制剂设计中的应用[J]. 药学学报, 2012,47(11): 1409-1422
21.高丽梅 张胜华 易 红 蒋建东 宋丹青.苯甲酰脲类抗肿瘤β微管蛋白抑制剂药效团模型的构建与应用[J]. 药学学报, 2010,45(4): 462-466
22.吴文, 卢骋, 陈思宇, 余聂芳.已上市和部分正在Ⅲ期临床开发中的多靶点激酶抑制剂抑酶谱及信号传导通路分析[J]. 药学学报, 2009,44(3): 242-257
23.姜凤超.多靶点作用药物及其设计[J]. 药学学报, 2009,44(3): 282-287
24.汤湧;张大永;吴晓明.作用于Bcl-2家族抗凋亡亚族蛋白的小分子抑制剂的研究进展[J]. 药学学报, 2008,43(7): 669-677
25.祝勇;童心玥;赵玥;陈卉;姜凤超.乙酰胆碱酯酶抑制剂药效团模型的构建[J]. 药学学报, 2008,43(3): 267-276
26.邓小强;向明礼;贾若;杨胜勇.选择性的激酶ATP竞争性抑制剂设计研究进展[J]. 药学学报, 2007,42(12): 1232-1236
27.张文婷;鄢浩;姜凤超.聚腺苷二磷酸核糖聚合酶-1抑制剂药效团模型的建立[J]. 药学学报, 2007,42(3): 279-285