Peterson Randall T, Shaw Stanley Y, Peterson Travis A, Milan David J, Zhong Tao P, Schreiber Stuart L, MacRae Calum A, Fishman Mark C
Nat Biotechnol. 2004 May;22(5):595-9. doi: 10.1038/nbt963. Epub 2004 Apr 18.
Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype. Phenotype-based screens offer the potential to identify pathways and potential therapies that influence disease processes. The zebrafish mutation gridlock (grl, affecting the gene hey2) disrupts aortic blood flow in a region and physiological manner akin to aortic coarctation in humans. Here we use a whole-organism, phenotype-based, small-molecule screen to discover a class of compounds that suppress the coarctation phenotype and permit survival to adulthood. These compounds function during the specification and migration of angioblasts. They act to upregulate expression of vascular endothelial growth factor (VEGF), and the activation of the VEGF pathway is sufficient to suppress the gridlock phenotype. Thus, organism-based screens allow the discovery of small molecules that ameliorate complex dysmorphic syndromes even without targeting the affected gene directly.
传统的药物发现方法需要事先选择合适的分子靶点，但往往不清楚必须针对哪些生物学途径来逆转疾病表型。基于表型的筛选提供了识别影响疾病进程的途径和潜在疗法的可能性。斑马鱼突变体gridlock（grl，影响基因hey2）以类似于人类主动脉缩窄的区域和生理方式破坏主动脉血流。在这里，我们使用全生物体、基于表型的小分子筛选来发现一类抑制缩窄表型并使鱼存活至成年的化合物。这些化合物在成血管细胞的特化和迁移过程中发挥作用。它们的作用是上调血管内皮生长因子（VEGF）的表达，并且VEGF途径的激活足以抑制gridlock表型。因此，基于生物体的筛选能够发现即使不直接针对受影响基因也能改善复杂畸形综合征的小分子。
