Mishra Manasi, Singh Vigyasa, Singh Shailja
Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Dadri, India.
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
Front Microbiol. 2019 Mar 5;10:394. doi: 10.3389/fmicb.2019.00394. eCollection 2019.
Malaria, caused by protozoan of genus , remains one of the highest mortality infectious diseases. Malaria parasites have a complex life cycle, easily adapt to their host's immune system and have evolved with an arsenal of unique proteases which play crucial roles in proliferation and survival within the host cells. Owing to the existing knowledge of enzymatic mechanisms, 3D structures and active sites of proteases, they have been proven to be opportune for target based drug development. Here, we discuss in depth the crucial roles of essential proteases in life cycle and particularly focus on highlighting the atypical "structural signatures" of key parasite proteases which have been exploited for drug development. These features, on one hand aid parasites pathogenicity while on the other hand could be effective in designing targeted and very specific inhibitors for counteracting them. We conclude that proteases are suitable as multistage targets for designing novel drugs with new modes of action to combat malaria.
由疟原虫属原生动物引起的疟疾仍然是致死率最高的传染病之一。疟原虫具有复杂的生命周期，很容易适应宿主的免疫系统，并且进化出了一系列独特的蛋白酶，这些蛋白酶在宿主细胞内的增殖和存活中起着关键作用。由于对蛋白酶的酶促机制、三维结构和活性位点已有了解，它们已被证明适合基于靶点的药物开发。在此，我们深入讨论必需蛋白酶在疟原虫生命周期中的关键作用，并特别着重强调已被用于药物开发的关键寄生虫蛋白酶的非典型“结构特征”。这些特征一方面有助于寄生虫的致病性，另一方面可有效地设计靶向且非常特异的抑制剂来对抗它们。我们得出结论，疟原虫蛋白酶适合作为多阶段靶点，用于设计具有新作用模式的新型抗疟药物。
