Department of Pediatrics, University of California, San Diego, School of Medicine , 9500 Gilman Drive 0741, La Jolla, California 92093, United States.
J Med Chem. 2013 Oct 24;56(20):7761-71. doi: 10.1021/jm400325j. Epub 2013 Sep 6.
Although phenotypic cellular screening has been used to drive antimalarial drug discovery in recent years, in some cases target-based drug discovery remains more attractive. This is especially true when appropriate high-throughput cellular assays are lacking, as is the case for drug discovery efforts that aim to provide a replacement for primaquine (4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine), the only drug that can block Plasmodium transmission to Anopheles mosquitoes and eliminate liver-stage hypnozoites. At present, however, there are no known chemically validated parasite protein targets that are important in all Plasmodium parasite developmental stages and that can be used in traditional biochemical compound screens. We propose that a plethora of novel, chemically validated, cross-stage antimalarial targets still remain to be discovered from the ~5,500 proteins encoded by the Plasmodium genomes. Here we discuss how in vitro evolution of drug-resistant strains of Plasmodium falciparum and subsequent whole-genome analysis can be used to find the targets of some of the many compounds discovered in whole-cell phenotypic screens.
尽管表型细胞筛选近年来已被用于推动抗疟药物的发现，但在某些情况下，基于靶点的药物发现仍然更具吸引力。当缺乏适当的高通量细胞检测时尤其如此，例如旨在寻找替代伯氨喹（4-N-（6-甲氧基喹啉-8-基）戊烷-1,4-二胺）的药物发现工作就是如此，伯氨喹是唯一能够阻止疟原虫传播给按蚊并消除肝期休眠子的药物。然而，目前尚没有已知的经过化学验证的寄生虫蛋白靶点，这些靶点在所有疟原虫发育阶段都很重要，并且可以用于传统的生化化合物筛选。我们提出，从约 5500 种由疟原虫基因组编码的蛋白质中，仍然有大量的新型、经过化学验证的、跨阶段的抗疟靶点有待发现。在这里，我们讨论了如何通过体外筛选抗疟药物耐药株的疟原虫，并进行全基因组分析，以找到全细胞表型筛选中发现的许多化合物的靶点。
