Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3052, Australia.
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3052, Australia.
Trends Parasitol. 2020 Jun;36(6):533-544. doi: 10.1016/j.pt.2020.03.006. Epub 2020 Apr 17.
Artemisinins - the frontline antimalarial drug class - are compromised by emerging resistance, putting at risk the lives of hundreds of thousands of people each year. Resistance is associated with mutations in a malaria parasite protein, called Kelch 13 (K13). Recent work suggests that K13 is located at the cytostome (cell mouth) that the parasite uses to take up hemoglobin. Here we explore the proposal that K13 mutations confer artemisinin resistance by dampening hemoglobin endocytosis. This model suggests that the resultant decrease in hemoglobin-derived heme reduces artemisinin activation, which is sufficient to enable parasite survival in the early ring stage of infection. A fuller understanding of the resistance mechanism will underpin efforts to develop alternative antimalarial strategies.
青蒿素类药物——作为一线抗疟药物——受到耐药性的威胁，每年危及数十万人的生命。耐药性与疟原虫蛋白 Kelch 13（K13）的突变有关。最近的研究表明，K13 位于疟原虫用来摄取血红蛋白的胞饮口（细胞口）。在这里，我们探讨了 K13 突变通过抑制血红蛋白内吞作用从而赋予青蒿素耐药性的假说。该模型表明，血红蛋白衍生的血红素减少导致青蒿素激活减少，这足以使寄生虫在感染的早期环阶段存活。对耐药机制的更全面理解将为开发替代抗疟策略提供支持。
