BK病毒大T抗原ATP结合位点作为药物研发靶点的验证
Validation of BKV large T-antigen ATP-binding site as a target for drug discovery.
作者信息
Zeng Gang, Bueno Marta, Camachos Carlos J, Ramaswami Bala, Luo Chunqing, Randhawa Parmjeet
机构信息
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
出版信息
Antiviral Res. 2009 Feb;81(2):184-7. doi: 10.1016/j.antiviral.2008.11.004. Epub 2008 Dec 11.
Abstract
BK virus large T antigen (LTA) is a hexameric protein with a helicase activity that is powered by ATP hydrolysis. A mutant virus with Lys420Ala, Arg421Ala, and Asp504Ala mutations at the ATP binding sites showed marked reduction in viral fitness. This observation indicates that high throughput screening for ATPase inhibitors will be valid strategy to discover anti-BKV drugs. Pilot screening of 300 compounds from the Tim Tec ActiTarg K library identified a compound, STO18584, with selectivity index of 19.2.
摘要
BK病毒大T抗原（LTA）是一种具有解旋酶活性的六聚体蛋白，其活性由ATP水解提供能量。一种在ATP结合位点发生赖氨酸420突变为丙氨酸、精氨酸421突变为丙氨酸以及天冬氨酸504突变为丙氨酸的突变病毒，其病毒适应性显著降低。这一观察结果表明，高通量筛选ATP酶抑制剂将是发现抗BK病毒药物的有效策略。对Tim Tec ActiTarg K文库中的300种化合物进行初步筛选，确定了一种名为STO18584的化合物，其选择性指数为19.2。
相似文献
1
Validation of BKV large T-antigen ATP-binding site as a target for drug discovery.BK病毒大T抗原ATP结合位点作为药物研发靶点的验证
Antiviral Res. 2009 Feb;81(2):184-7. doi: 10.1016/j.antiviral.2008.11.004. Epub 2008 Dec 11.
2
Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs.抑制大T抗原ATP酶活性作为开发抗多瘤病毒JC药物的潜在策略。
Antiviral Res. 2014 Dec;112:113-9. doi: 10.1016/j.antiviral.2014.10.004. Epub 2014 Oct 15.
3
A screen for modulators of large T antigen's ATPase activity uncovers novel inhibitors of Simian Virus 40 and BK virus replication.一种用于筛选大 T 抗原 ATP 酶活性调节剂的方法揭示了新型的猴病毒 40 和 BK 病毒复制抑制剂。
Antiviral Res. 2012 Oct;96(1):70-81. doi: 10.1016/j.antiviral.2012.07.012. Epub 2012 Aug 7.
4
Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.
J Med Chem. 2016 Aug 11;59(15):7138-51. doi: 10.1021/acs.jmedchem.6b00486. Epub 2016 Jul 20.
5
Systematic study of the functions for the residues around the nucleotide pocket in simian virus 40 AAA+ hexameric helicase.猿猴病毒40 AAA+六聚体解旋酶中核苷酸口袋周围残基功能的系统研究。
J Virol. 2008 Jun;82(12):6017-23. doi: 10.1128/JVI.00387-08. Epub 2008 Apr 9.
6
Simian virus 40 large T antigen can specifically unwind the central palindrome at the origin of DNA replication.猴病毒40大T抗原可特异性解开DNA复制起点处的中心回文序列。
J Virol. 2009 Apr;83(7):3312-22. doi: 10.1128/JVI.01867-08. Epub 2009 Jan 14.
7
Effects of therapy using a helicase-primase inhibitor (HPI) in mice infected with deliberate mixtures of wild-type HSV-1 and an HPI-resistant UL5 mutant.在故意混合感染野生型 HSV-1 和 HPI 抗性 UL5 突变体的小鼠中使用解旋酶-引发酶抑制剂（HPI）进行治疗的效果。
Antiviral Res. 2010 Jul;87(1):67-73. doi: 10.1016/j.antiviral.2010.04.008. Epub 2010 Apr 24.
8
trans-Dominant and non-trans-dominant mutant simian virus 40 large T antigens show distinct responses to ATP.反式显性和非反式显性突变猿猴病毒40大T抗原对ATP表现出不同反应。
J Virol. 1997 Oct;71(10):7549-59. doi: 10.1128/JVI.71.10.7549-7559.1997.
9
Discovering new medicines targeting helicases: challenges and recent progress.发现靶向解旋酶的新药：挑战与最新进展。
J Biomol Screen. 2013 Aug;18(7):761-81. doi: 10.1177/1087057113482586. Epub 2013 Mar 27.
10
UL52 primase interactions in the herpes simplex virus 1 helicase-primase are affected by antiviral compounds and mutations causing drug resistance.单纯疱疹病毒1型解旋酶-引发酶中UL52引发酶的相互作用受抗病毒化合物和导致耐药性的突变影响。
J Biol Chem. 2014 Nov 21;289(47):32583-92. doi: 10.1074/jbc.M114.609453. Epub 2014 Oct 2.
引用本文的文献
1
Establishment of a Stable BK Polyomavirus-Secreting Cell Line: Characterization of Viral Genome Integration and Replication Dynamics Through Comprehensive Analysis.建立稳定分泌BK多瘤病毒的细胞系：通过综合分析对病毒基因组整合和复制动力学进行表征
Int J Mol Sci. 2025 Jun 15;26(12):5745. doi: 10.3390/ijms26125745.
2
Reining in polyoma virus associated nephropathy: design and characterization of a template mimicking BK viral coat protein cellular binding.抑制多瘤病毒相关性肾病：模拟 BK 病毒外壳蛋白细胞结合的模板的设计和特性。
Biochemistry. 2012 Oct 16;51(41):8092-9. doi: 10.1021/bi300639d. Epub 2012 Oct 2.
本文引用的文献
1
Systematic study of the functions for the residues around the nucleotide pocket in simian virus 40 AAA+ hexameric helicase.猿猴病毒40 AAA+六聚体解旋酶中核苷酸口袋周围残基功能的系统研究。
J Virol. 2008 Jun;82(12):6017-23. doi: 10.1128/JVI.00387-08. Epub 2008 Apr 9.
2
BK virus-associated hemorrhagic cystitis in pediatric cancer patients receiving high-dose cyclophosphamide.接受大剂量环磷酰胺治疗的儿科癌症患者中的BK病毒相关性出血性膀胱炎
J Pediatr Hematol Oncol. 2007 Sep;29(9):617-21. doi: 10.1097/MPH.0b013e3181461f6c.
3
Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation.肾移植受者中多瘤病毒BK与JC的复制及肾病：一项前瞻性评估
Transplantation. 2007 Aug 15;84(3):323-30. doi: 10.1097/01.tp.0000269706.59977.a5.
4
Phylogenetic analysis of polyomavirus BK sequences.多瘤病毒BK序列的系统发育分析
J Virol. 2006 Sep;80(18):8869-79. doi: 10.1128/JVI.00510-06.
5
Prevalence of BK virus replication among recipients of solid organ transplants.实体器官移植受者中BK病毒复制的患病率。
Clin Infect Dis. 2005 Dec 15;41(12):1720-5. doi: 10.1086/498118. Epub 2005 Nov 10.
6
Monitoring for polyomavirus BK And JC in urine: comparison of quantitative polymerase chain reaction with urine cytology.尿液中多瘤病毒BK和JC的监测：定量聚合酶链反应与尿细胞学检查的比较
Transplantation. 2005 Apr 27;79(8):984-6. doi: 10.1097/01.tp.0000157573.90090.fd.
7
Insights into hRPA32 C-terminal domain--mediated assembly of the simian virus 40 replisome.对人源复制蛋白A32（hRPA32）羧基末端结构域介导的猿猴病毒40（SV40）复制体组装的见解
Nat Struct Mol Biol. 2005 Apr;12(4):332-9. doi: 10.1038/nsmb916. Epub 2005 Mar 27.
8
Effect of leflunomide and cidofovir on replication of BK virus in an in vitro culture system.来氟米特和西多福韦对BK病毒在体外培养系统中复制的影响。
Transplantation. 2005 Jan 15;79(1):116-8. doi: 10.1097/01.tp.0000149338.97084.5f.
9
Mechanisms of conformational change for a replicative hexameric helicase of SV40 large tumor antigen.猴空泡病毒40大T抗原复制性六聚体解旋酶的构象变化机制
Cell. 2004 Oct 1;119(1):47-60. doi: 10.1016/j.cell.2004.09.017.
10
Insights into the oligomeric states, conformational changes, and helicase activities of SV40 large tumor antigen.对SV40大肿瘤抗原的寡聚状态、构象变化和解旋酶活性的深入了解。
J Biol Chem. 2004 Sep 10;279(37):38952-9. doi: 10.1074/jbc.M406160200. Epub 2004 Jul 9.
Zotero 插件