Sao Carlos Institute of Physics, University of Sao Paulo, PO Box 369, 13560-970, Sao Carlos, SP, Brazil.
Chemistry Department, Federal University of Goias - Catalao regional, 75704-020, Catalao - GO, Brazil.
Curr Med Chem. 2019;26(23):4380-4402. doi: 10.2174/0929867324666170830103003.
Malaria remains a major health problem, especially because of the emergence of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and affordable antimalarial drugs are desperately needed. New proteins have been investigated as molecular targets for research and development of innovative compounds with welldefined mechanism of action. In this review, we highlight genetically and clinically validated plasmodial proteins as drug targets for the next generation of therapeutics. The enzymes described herein are involved in hemoglobin hydrolysis, the invasion process, elongation factors for protein synthesis, pyrimidine biosynthesis, post-translational modifications such as prenylation, phosphorylation and histone acetylation, generation of ATP in mitochondrial metabolism and aminoacylation of RNAs. Significant advances on proteomics, genetics, structural biology, computational and biophysical methods provided invaluable molecular and structural information about these drug targets. Based on this, several strategies and models have been applied to identify and improve lead compounds. This review presents the recent progresses in the discovery of antimalarial drug candidates, highlighting the approaches, challenges, and perspectives to deliver affordable, safe and low single-dose medicines to treat malaria.
疟疾仍然是一个主要的健康问题，特别是由于抗青蒿素衍生物的恶性疟原虫株的出现。在这种情况下，急需安全且负担得起的抗疟药物。人们已经研究了新的蛋白质作为分子靶点，以开发具有明确作用机制的创新化合物。在这篇综述中，我们强调了经过基因和临床验证的疟原虫蛋白作为下一代治疗药物的靶标。本文所述的酶参与血红蛋白水解、入侵过程、蛋白质合成的延伸因子、嘧啶生物合成、翻译后修饰如 prenylation、磷酸化和组蛋白乙酰化、线粒体代谢中的 ATP 生成以及 RNA 的氨酰化。蛋白质组学、遗传学、结构生物学、计算和生物物理方法的显著进展为这些药物靶点提供了宝贵的分子和结构信息。在此基础上，已经应用了多种策略和模型来识别和改进先导化合物。本文介绍了抗疟药物候选物发现的最新进展，强调了提供负担得起、安全和低单剂量药物治疗疟疾的方法、挑战和前景。
