National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, 080-8555, Japan.
College of Animal Science and Technology, Inner Mongolia University For Nationalities, Tongliao, 028000, Inner Mongolia, People's Republic of China.
Parasitol Res. 2020 May;119(5):1675-1681. doi: 10.1007/s00436-020-06673-9. Epub 2020 Apr 1.
Toxoplasma gondii can infect virtually all warm-blooded animals, including humans. It can differentiate between rapidly replicating tachyzoites that cause acute infection and slowly growing bradyzoites in tissue cysts. Treatment options for toxoplasmosis are challenging because current therapies cannot eradicate the latent T. gondii infection that is mainly caused by the bradyzoite forms. Accordingly, recurrence of infection is a problem for immunocompromised patients and congenitally infected patients. Protein kinases have been widely studied in eukaryotic cells, and while little is known about signaling in Toxoplasma infection, it is likely that protein kinases play a key role in parasite proliferation, differentiation, and probably invasion. To identify optimized new kinase inhibitors for drug development against T. gondii, we screened a library of kinase inhibitor compounds for anti-Toxoplasma activity and host cell cytotoxicity. Pyrimethamine served as a positive control and 0.5% DMSO was used as a negative control. Among the 80 compounds screened, 6 compounds demonstrated ≥ 80% parasite growth inhibition at concentrations at which 5 compounds did not suppress host cell viability, while 3 kinase inhibitors (Bay 11-7082, Tyrphostin AG 1295 and PD-98059) had suppressive effects individually on parasite growth and host cell invasion, but did not strongly induce bradyzoite formation.
刚地弓形虫几乎可以感染所有温血动物，包括人类。它可以在快速复制的速殖子引起急性感染和组织囊肿中缓慢生长的缓殖子之间进行区分。弓形虫病的治疗选择具有挑战性，因为目前的治疗方法无法消除主要由缓殖子形式引起的潜伏性 T. gondii 感染。因此，感染的复发是免疫功能低下患者和先天性感染患者的一个问题。蛋白激酶在真核细胞中得到了广泛研究，虽然对于弓形虫感染中的信号转导知之甚少，但蛋白激酶很可能在寄生虫增殖、分化，可能还有入侵中发挥关键作用。为了鉴定针对 T. gondii 的优化新型激酶抑制剂以用于药物开发，我们筛选了激酶抑制剂化合物文库以检测其抗弓形虫活性和宿主细胞细胞毒性。乙胺嘧啶作为阳性对照，0.5% DMSO 作为阴性对照。在筛选的 80 种化合物中，有 6 种化合物在浓度下对寄生虫生长的抑制率≥80%，而 5 种化合物不抑制宿主细胞活力，同时 3 种激酶抑制剂（Bay 11-7082、Tyrphostin AG 1295 和 PD-98059）单独对寄生虫生长和宿主细胞入侵具有抑制作用，但不会强烈诱导缓殖子形成。
