英国格拉斯哥大学Andrew B. Tobin研究组鉴定到蛋白激酶PfCLK3可在疟原虫的多个生长阶段以及不同种的疟原虫中作为有效的疟疾药物靶点。相关论文于2019年8月30日发表在《科学》杂志上。
研究人员鉴定了恶性疟原虫蛋白激酶PfCLK3的选择性抑制剂，研究人员将其与化学遗传学结合使用验证到PfCLK3是能够在多个寄生虫生命阶段起作用的药物靶标。与PfCLK3在RNA剪接中的作用一致，抑制这个蛋白导致超过400个寄生虫必需基因的下调。抑制PfCLK3能够快速杀死处在肝脏和血液阶段的无性生殖恶性疟原虫并阻止配子体发育，从而防止传播，并且这还显示出对伯氏疟原虫和诺氏疟原虫的寄生虫杀灭活性。因此，这些数据确定PfCLK3能够作为药物目标，有可能提供新的治疗方案，即预防和传播阻断疟疾。
据了解，下一代抗疟药既要能够治愈又需要传播阻断，因此这需要鉴定以前未发现的可制药分子途径。
附：英文原文
Title: Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target
Author: Mahmood M. Alam, Ana Sanchez-Azqueta, Omar Janha, Erika L. Flannery, Amit Mahindra, Kopano Mapesa, Aditya B. Char, Dev Sriranganadane, Nicolas M. B. Brancucci, Yevgeniya Antonova-Koch, Kathryn Crouch, Nelson Victor Simwela, Scott B. Millar, Jude Akinwale, Deborah Mitcheson, Lev Solyakov, Kate Dudek, Carolyn Jones, Cleofé Zapatero, Christian Doerig, Davis C. Nwakanma, Maria Jesús Vázquez, Gonzalo Colmenarejo, Maria Jose Lafuente-Monasterio, Maria Luisa Leon, Paulo H. C. Godoi, Jon M. Elkins, Andrew P. Waters, Andrew G. Jamieson, Elena Fernández álvaro, Lisa C. Ranford-Cartwright, Matthias Marti, Elizabeth A. Winzeler, Francisco Javier Gamo, Andrew B. Tobin
Issue&Volume: Volume 365 Issue 6456, 2019/08/30
Abstract: The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase PfCLK3, which we used in combination with chemogenetics to validate PfCLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for PfCLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of PfCLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi. Hence, our data establish PfCLK3 as a target for drugs, with the potential to offer a cure—to be prophylactic and transmission blocking in malaria.
DOI: 10.1126/science.aau1682
Source: https://science.sciencemag.org/content/365/6456/eaau1682