吡啶嘧啶酮作为隐孢子虫钙依赖蛋白激酶 1 (CDPK1) 抑制剂的新化学类型。

IF 1.4 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Elise Waldron-Young , Wissarut Wijitrmektong , Ryan Choi , Grant R. Whitman , Matthew A. Hulverson , Raheela Charania , Aidan Keelaghan , Li Li , Songpol Srinual , Sameer Nikhar , Case W. McNamara , Melissa S. Love , Lauren Huerta , Malina A. Bakowski , Ming Hu , Wesley C. Van Voorhis , Jan R. Mead , Gregory D. Cuny
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引用次数: 0

摘要

原生动物蛋白激酶钙依赖性蛋白激酶 1(CDPK1)已成为治疗隐孢子虫病的潜在治疗靶标。对已知激酶抑制剂的集中筛选发现,吡啶嘧啶酮是一种新的副隐孢子虫(Cp)CDPK1抑制剂化学类型。将 CpCDPK1 与两种具有代表性的人类激酶 RIPK2 和 Src 进行结构比较后发现,两者在 αC 螺旋的位置上存在差异。k.a. UH15-16,IC50 = 10nM),它能阻断三种副猪嗜血杆菌菌株(EC50 = 12-40nM)和人嗜血杆菌(EC50 = 85nM)在 HCT-8 宿主细胞中的生长。药代动力学和组织分布分析表明,口服 7 后的全身暴露量低,但胃肠道浓度高,Caco-2 细胞渗透性好。最后,7 在 IL-12 基因敲除的急性隐孢子虫病小鼠模型中显示出部分疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium

Pyridopyrimidinones as a new chemotype of calcium dependent protein kinase 1 (CDPK1) inhibitors for Cryptosporidium

The protozoan protein kinase calcium-dependent protein kinase 1 (CDPK1) has emerged as a potential therapeutic target for the treatment of cryptosporidiosis. A focused screen of known kinase inhibitors identified a pyridopyrimidinone as a new chemotype of Cryptosporidium parvum (Cp) CDPK1 inhibitors. Structural comparison of CpCDPK1 to two representative human kinases, RIPK2 and Src, revealed differences in the positioning of the αC-helix that was used in the design of a potent pyridopyrimidinone-based CpCDPK1 inhibitor 7 (a.k.a. UH15–16, IC50 = 10 nM), which blocked the growth of three C. parvum strains (EC50 = 12–40 nM) as well as C. hominis (EC50 = 85 nM) in HCT-8 host cells. Pharmacokinetic and tissue distribution analyses indicated that 7 had low systemic exposure after oral administration, but high gastrointestinal concentration, as well as good Caco-2 cell permeability. Finally, 7 demonstrated partial efficacy in an IL-12 knock-out mouse model of acute cryptosporidiosis.

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来源期刊
CiteScore
2.90
自引率
0.00%
发文量
51
审稿时长
63 days
期刊介绍: The journal provides a medium for rapid publication of investigations of the molecular biology and biochemistry of parasitic protozoa and helminths and their interactions with both the definitive and intermediate host. The main subject areas covered are: • the structure, biosynthesis, degradation, properties and function of DNA, RNA, proteins, lipids, carbohydrates and small molecular-weight substances • intermediary metabolism and bioenergetics • drug target characterization and the mode of action of antiparasitic drugs • molecular and biochemical aspects of membrane structure and function • host-parasite relationships that focus on the parasite, particularly as related to specific parasite molecules. • analysis of genes and genome structure, function and expression • analysis of variation in parasite populations relevant to genetic exchange, pathogenesis, drug and vaccine target characterization, and drug resistance. • parasite protein trafficking, organelle biogenesis, and cellular structure especially with reference to the roles of specific molecules • parasite programmed cell death, development, and cell division at the molecular level.
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