bumped 激酶抑制剂作为治疗顶复门寄生虫病的药物：经验教训。
Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned.
机构信息
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
出版信息
Int J Parasitol. 2020 May;50(5):413-422. doi: 10.1016/j.ijpara.2020.01.006. Epub 2020 Mar 26.
Abstract
Bumped Kinase Inhibitors, targeting Calcium-dependent Protein Kinase 1 in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology that have shaped our selection of pre-clinical candidates.
摘要
Bumped 激酶抑制剂靶向顶复门原虫中的钙依赖性蛋白激酶 1，其甘氨酸门控结构使其成为顶复门原虫疾病的有前途的新型治疗药物。在此，我们将回顾在疗效、安全性和药理学方面的进展、挑战和经验教训，这些因素影响了我们对临床前候选药物的选择。
相似文献
1
Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned. bumped 激酶抑制剂作为治疗顶复门寄生虫病的药物：经验教训。
Int J Parasitol. 2020 May;50(5):413-422. doi: 10.1016/j.ijpara.2020.01.006. Epub 2020 Mar 26.
2
One health therapeutics: Target-Based drug development for cryptosporidiosis and other apicomplexa diseases.一体健康疗法：隐孢子虫病和其他顶复门寄生虫病的基于靶点的药物研发。
Vet Parasitol. 2021 Jan;289:109336. doi: 10.1016/j.vetpar.2020.109336. Epub 2020 Dec 15.
3
Selective inhibition of Sarcocystis neurona calcium-dependent protein kinase 1 for equine protozoal myeloencephalitis therapy.用于马原虫性脑脊髓炎治疗的对马肉孢子虫钙依赖性蛋白激酶1的选择性抑制
Int J Parasitol. 2016 Dec;46(13-14):871-880. doi: 10.1016/j.ijpara.2016.08.003. Epub 2016 Oct 8.
4
Bumped kinase inhibitor 1294 treats established Toxoplasma gondii infection.撞击激酶抑制剂1294可治疗已有的弓形虫感染。
Antimicrob Agents Chemother. 2014 Jun;58(6):3547-9. doi: 10.1128/AAC.01823-13. Epub 2014 Mar 31.
5
Extended-spectrum antiprotozoal bumped kinase inhibitors: A review.广谱抗原生动物激酶抑制剂：综述
Exp Parasitol. 2017 Sep;180:71-83. doi: 10.1016/j.exppara.2017.01.001. Epub 2017 Jan 5.
6
Efficacy of the bumped kinase inhibitor BKI-1708 against the cyst-forming apicomplexan parasites Toxoplasma gondii and Neospora caninum in vitro and in experimentally infected mice.碰撞激酶抑制剂BKI-1708对形成包囊的顶复门寄生虫刚地弓形虫和犬新孢子虫的体外及实验性感染小鼠的疗效
Int J Parasitol Drugs Drug Resist. 2024 Aug;25:100553. doi: 10.1016/j.ijpddr.2024.100553. Epub 2024 Jun 19.
7
In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum.碰撞激酶抑制剂1294对相关形成囊肿的顶复门原虫刚地弓形虫和犬新孢子虫的体外及体内作用
Antimicrob Agents Chemother. 2015 Oct;59(10):6361-74. doi: 10.1128/AAC.01236-15. Epub 2015 Jul 27.
8
Recent developments in drug discovery against the protozoal parasites Cryptosporidium and Toxoplasma.抗原生动物寄生虫隐孢子虫和弓形虫药物研发的最新进展。
Bioorg Med Chem Lett. 2017 Apr 1;27(7):1491-1501. doi: 10.1016/j.bmcl.2017.01.046. Epub 2017 Jan 17.
9
Roles of Apicomplexan protein kinases at each life cycle stage.顶复门蛋白激酶在每个生命周期阶段的作用。
Parasitol Int. 2012 Jun;61(2):224-34. doi: 10.1016/j.parint.2011.12.002. Epub 2011 Dec 24.
10
Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice. bumped kinase 抑制剂对早期斑马鱼胚胎发育和小鼠妊娠影响的比较评估。
Int J Antimicrob Agents. 2020 Sep;56(3):106099. doi: 10.1016/j.ijantimicag.2020.106099. Epub 2020 Jul 21.
引用本文的文献
1
Anti-Cryptosporidium efficacy of BKI-1708, an inhibitor of Cryptosporidium calcium-dependent protein kinase 1.隐孢子虫钙依赖性蛋白激酶1抑制剂BKI-1708的抗隐孢子虫功效
PLoS Negl Trop Dis. 2025 Jul 30;19(7):e0013263. doi: 10.1371/journal.pntd.0013263. eCollection 2025 Jul.
2
Bumped Kinase Inhibitors Inhibit both MAPKL1 and CDPK1.碰撞激酶抑制剂可同时抑制MAPKL1和CDPK1。
ACS Infect Dis. 2025 Jun 13;11(6):1552-1562. doi: 10.1021/acsinfecdis.5c00051. Epub 2025 May 23.
3
Treatment with BKI-1748 after systemic dissemination in experimentally infected pregnant sheep improves fetal and lamb mortality and morbidity and prevents congenital infection.在实验性感染的怀孕绵羊全身播散后用BKI-1748进行治疗可改善胎儿和羔羊的死亡率及发病率，并预防先天性感染。
Antimicrob Agents Chemother. 2025 Feb 13;69(2):e0144824. doi: 10.1128/aac.01448-24. Epub 2024 Dec 31.
4
Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium.作为隐孢子虫钙依赖性蛋白激酶1（CDPK1）抑制剂新化学类型的吡啶并嘧啶酮类化合物。
Mol Biochem Parasitol. 2024 Dec;260:111637. doi: 10.1016/j.molbiopara.2024.111637. Epub 2024 Jun 18.
5
Molecular Targets of the 5-Amido-Carboxamide Bumped Kinase Inhibitor BKI-1748 in and HCT-8 Host Cells.在 和 HCT-8 宿主细胞中 5-酰胺基羧酰胺 bumped 激酶抑制剂 BKI-1748 的分子靶标。
Int J Mol Sci. 2024 Feb 26;25(5):2707. doi: 10.3390/ijms25052707.
6
Genomic and virulence analysis of in vitro cultured Cryptosporidium parvum.体外培养的微小隐孢子虫的基因组和毒力分析
PLoS Pathog. 2024 Feb 28;20(2):e1011992. doi: 10.1371/journal.ppat.1011992. eCollection 2024 Feb.
7
Anti-Cryptosporidial Drug-Discovery Challenges and Existing Therapeutic Avenues: A "One-Health" Concern.抗隐孢子虫药物研发的挑战与现有治疗途径：一个“同一健康”问题
Life (Basel). 2024 Jan 3;14(1):80. doi: 10.3390/life14010080.
8
Single and combination treatment of Toxoplasma gondii infections with a bumped kinase inhibitor and artemisone in vitro and with artemiside in experimentally infected mice.弓形虫感染的单药和联合治疗： bumped 激酶抑制剂与青蒿素及其衍生物在体外和实验感染小鼠体内的研究
Exp Parasitol. 2023 Dec;255:108655. doi: 10.1016/j.exppara.2023.108655. Epub 2023 Nov 18.
9
An Early Treatment With BKI-1748 Exhibits Full Protection Against Abortion and Congenital Infection in Sheep Experimentally Infected With Toxoplasma gondii.经 BKI-1748 早期治疗可完全预防弓形虫感染绵羊的流产和先天感染。
J Infect Dis. 2024 Feb 14;229(2):558-566. doi: 10.1093/infdis/jiad470.
10
Structure-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633.抗隐孢子虫先导化合物 SLU-2633 的三唑并嘧啶替换物的构效关系。
Bioorg Med Chem. 2023 May 15;86:117295. doi: 10.1016/j.bmc.2023.117295. Epub 2023 Apr 28.
本文引用的文献
1
P-Glycoprotein-Mediated Efflux Reduces the In Vivo Efficacy of a Therapeutic Targeting the Gastrointestinal Parasite Cryptosporidium.P-糖蛋白介导的外排降低了靶向胃肠道寄生虫隐孢子虫的治疗药物的体内疗效。
J Infect Dis. 2019 Aug 30;220(7):1188-1198. doi: 10.1093/infdis/jiz269.
2
Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro. bumped 激酶抑制剂 1369 对体内外猪等孢球虫具有疗效。
Int J Parasitol Drugs Drug Resist. 2019 Aug;10:9-19. doi: 10.1016/j.ijpddr.2019.03.004. Epub 2019 Apr 2.
3
Development of 5-Aminopyrazole-4-carboxamide-based Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.基于 5-氨基吡唑-4-甲酰胺的 bumped-kinase 抑制剂的开发用于隐孢子虫病的治疗。
J Med Chem. 2019 Mar 28;62(6):3135-3146. doi: 10.1021/acs.jmedchem.9b00069. Epub 2019 Mar 15.
4
Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis.吡唑并嘧啶、吡咯并嘧啶和 5-氨基吡唑-4-甲酰胺 bumped 激酶抑制剂对弓形虫病的药代动力学和体内疗效。
J Infect Dis. 2019 Apr 16;219(9):1464-1473. doi: 10.1093/infdis/jiy664.
5
7 H-Pyrrolo[2,3- d]pyrimidin-4-amine-Based Inhibitors of Calcium-Dependent Protein Kinase 1 Have Distinct Inhibitory and Oral Pharmacokinetic Characteristics Compared with 1 H-Pyrazolo[3,4- d]pyrimidin-4-amine-Based Inhibitors.与基于1H-吡唑并[3,4-d]嘧啶-4-胺的抑制剂相比，基于7H-吡咯并[2,3-d]嘧啶-4-胺的钙依赖性蛋白激酶1抑制剂具有不同的抑制特性和口服药代动力学特征。
ACS Infect Dis. 2018 Apr 13;4(4):516-522. doi: 10.1021/acsinfecdis.7b00224. Epub 2018 Mar 16.
6
Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis. bumped 激酶抑制剂在人类和动物隐孢子虫病治疗中的研究进展。
Int J Parasitol. 2017 Oct;47(12):753-763. doi: 10.1016/j.ijpara.2017.08.006. Epub 2017 Sep 9.
7
Necessity of Bumped Kinase Inhibitor Gastrointestinal Exposure in Treating Cryptosporidium Infection.激酶抑制剂胃肠道暴露在治疗隐孢子虫感染中的必要性。
J Infect Dis. 2017 Jul 1;216(1):55-63. doi: 10.1093/infdis/jix247.
8
5-Aminopyrazole-4-Carboxamide-Based Compounds Prevent the Growth of Cryptosporidium parvum.基于5-氨基吡唑-4-甲酰胺的化合物可抑制微小隐孢子虫的生长。
Antimicrob Agents Chemother. 2017 Jul 25;61(8). doi: 10.1128/AAC.00020-17. Print 2017 Aug.
9
Cryo-EM Structure of the Open Human Ether-à-go-go-Related K Channel hERG.开放型人类醚-去极化相关钾通道hERG的冷冻电镜结构
Cell. 2017 Apr 20;169(3):422-430.e10. doi: 10.1016/j.cell.2017.03.048.
10
Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.用于隐孢子虫病治疗的撞击激酶抑制剂
J Infect Dis. 2017 Apr 15;215(8):1275-1284. doi: 10.1093/infdis/jix120.
Zotero 插件