Reguera Rosa M, Calvo-Álvarez Estefanía, Alvarez-Velilla Raquel, Balaña-Fouce Rafael
Departamento de Ciencias Biomédicas, Universidad de León, Campus de Vegazana s/n, 24071 León, Spain.
Int J Parasitol Drugs Drug Resist. 2014 May 22;4(3):355-7. doi: 10.1016/j.ijpddr.2014.05.001. eCollection 2014 Dec.
Drug discovery programs sponsored by public or private initiatives pursue the same ambitious goal: a crushing defeat of major Neglected Tropical Diseases (NTDs) during this decade. Both target-based and target-free screenings have pros and cons when it comes to finding potential small-molecule leads among chemical libraries consisting of myriads of compounds. Within the target-based strategy, crystals of pathogen recombinant-proteins are being used to obtain three-dimensional (3D) structures in silico for the discovery of structure-based inhibitors. On the other hand, genetically modified parasites expressing easily detectable reporters are in the pipeline of target-free (phenotypic) screenings. Furthermore, lead compounds can be scaled up to in vivo preclinical trials using rodent models of infection monitoring parasite loads by means of cutting-edge bioimaging devices. As such, those preferred are fluorescent and bioluminescent readouts due to their reproducibility and rapidity, which reduces the number of animals used in the trials and allows for an earlier stage detection of the infective process as compared with classical methods. In this review, we focus on the current differences between target-based and phenotypic screenings in Leishmania, as an approach that leads to the discovery of new potential drugs against leishmaniasis.
在这十年内彻底战胜主要的被忽视热带病（NTDs）。在由无数化合物组成的化学文库中寻找潜在的小分子先导物时，基于靶点的筛选和非基于靶点的筛选都各有优缺点。在基于靶点的策略中，病原体重组蛋白的晶体被用于在计算机上获得三维（3D）结构，以发现基于结构的抑制剂。另一方面，表达易于检测的报告基因的转基因寄生虫正处于非基于靶点（表型）筛选的流程中。此外，先导化合物可以扩大规模进行体内临床前试验，使用啮齿动物感染模型，借助前沿生物成像设备监测寄生虫负荷。因此，由于其可重复性和快速性，荧光和生物发光读数是首选，与传统方法相比，这减少了试验中使用的动物数量，并允许在感染过程的早期阶段进行检测。在这篇综述中，我们聚焦于利什曼原虫中基于靶点的筛选和表型筛选之间的当前差异，作为一种发现抗利什曼病新潜在药物的方法。
