Lin Benjamin C, Harris Darcy R, Kirkman Lucy M D, Perez Astrid M, Qian Yiwen, Schermerhorn Janse T, Hong Min Y, Winston Dennis S, Xu Lingyin, Lieber Alexander M, Hamilton Matthew, Brandt Gabriel S
Department of Chemistry, Franklin & Marshall College, Lancaster, PA, United States.
Department of Chemistry, Franklin & Marshall College, Lancaster, PA, United States.
Bioorg Chem. 2017 Dec;75:217-223. doi: 10.1016/j.bioorg.2017.09.011. Epub 2017 Sep 18.
The FIKK family of kinases is unique to parasites of the Apicomplexan order, which includes all malaria parasites. Plasmodium falciparum, the most virulent form of human malaria, has a family of 19 FIKK kinases, most of which are exported into the host red blood cell during malaria infection. Here, we confirm that FIKK 8 is a non-exported member of the FIKK kinase family. Through expression and purification of the recombinant kinase domain, we establish that emodin is a relatively high-affinity (IC=2μM) inhibitor of PfFk8. Closely related anthraquinones do not inhibit PfFk8, suggesting that the particular substitution pattern of emodin is critical to the inhibitory pharmacophore. This first report of a P. falciparum FIKK kinase inhibitor lays the groundwork for developing specific inhibitors of the various members of the FIKK kinase family in order to probe their physiological function.
FIKK激酶家族是顶复门寄生虫所特有的，顶复门包括所有疟原虫。恶性疟原虫是人类疟疾中最具毒性的形式，有一个由19种FIKK激酶组成的家族，其中大多数在疟疾感染期间会输出到宿主红细胞中。在这里，我们证实FIKK 8是FIKK激酶家族的一个非输出成员。通过重组激酶结构域的表达和纯化，我们确定大黄素是PfFk8的一种相对高亲和力（IC = 2μM）抑制剂。密切相关的蒽醌不抑制PfFk8，这表明大黄素的特定取代模式对抑制药效团至关重要。这篇关于恶性疟原虫FIKK激酶抑制剂的首次报道为开发FIKK激酶家族各成员的特异性抑制剂以探究其生理功能奠定了基础。
