开发具有强效抗弓形虫活性的刚地弓形虫钙依赖蛋白激酶 1（TgCDPK1）抑制剂。
Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity.
机构信息
Department of Chemistry, University of Washington, Seattle, Washington, USA.
出版信息
J Med Chem. 2012 Mar 8;55(5):2416-26. doi: 10.1021/jm201713h. Epub 2012 Feb 27.
Abstract
Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
摘要
弓形虫病是一种严重的健康问题，由原生动物寄生虫刚地弓形虫引起。刚地弓形虫的增殖依赖于其侵入宿主细胞的能力，部分由钙依赖性蛋白激酶 1（CDPK1）介导。我们开发了 TgCDPK1 的 ATP 竞争抑制剂，该抑制剂可阻断寄生虫侵入宿主细胞，从而阻止其增殖。TgCDPK1 中存在独特的甘氨酸门控残基，允许选择性抑制寄生虫酶而不抑制人类激酶。这些强效的 TgCDPK1 抑制剂不会抑制人细胞系的生长，是弓形虫病治疗的有前途的候选药物。
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