New Molecular Targets and Strategies for Antimalarial Discovery

被引:17
作者
Aguiar, Anna Caroline [1 ]
de Sousa, Lorena R. F. [1 ,2 ]
Garcia, Celia R. S. [3 ]
Oliva, Glaucius [1 ]
Guido, Rafael V. C. [1 ]
机构
[1] Univ Sao Paulo, Sao Carlos Inst Phys, POB 369, BR-13560970 Sao Carlos, SP, Brazil
[2] Univ Fed Goias, Chem Dept, BR-75704020 Catalao, Go, Brazil
[3] Univ Sao Paulo, Biosci Inst, Physiol Dept, Sao Paulo, SP, Brazil
基金
巴西圣保罗研究基金会;
关键词
Plasmodium spp; malaria; enzymes; molecular target; antimalarial; inhibitor; FALCIPARUM DIHYDROOROTATE DEHYDROGENASE; SELECTIVE FARNESYLTRANSFERASE INHIBITORS; CYSTEINE PROTEASE FALCIPAIN-2; PLASMODIUM-FALCIPARUM; MALARIA PARASITE; DRUG DISCOVERY; ARTEMISININ RESISTANCE; ELECTRON-TRANSPORT; 3D-QSAR ANALYSIS; STRUCTURAL BASIS;
D O I
10.2174/0929867324666170830103003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 well-defined 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.
引用
收藏
页码:4380 / 4402
页数:23
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