a School of Environmental Science and Engineering , Shanghai Jiao Tong University , Shanghai , China.
b Shanghai Institute of Pollution Control and Ecological Security, Tongji University , Shanghai , China.
Expert Opin Drug Discov. 2019 Apr;14(4):343-353. doi: 10.1080/17460441.2019.1577815. Epub 2019 Mar 6.
Our understanding of the complexity of cardiovascular disease pathophysiology remains very incomplete and has hampered cardiovascular drug development over recent decades. The prevalence of cardiovascular diseases and their increasing global burden call for novel strategies to address disease biology and drug discovery. Areas covered: This review describes the recent history of cardiovascular drug discovery using in vivo phenotype-based screening in zebrafish. The rationale for the use of this model is highlighted and the initial efforts in the fields of disease modeling and high-throughput screening are illustrated. Finally, the advantages and limitations of in vivo zebrafish screening are discussed, highlighting newer approaches, such as genome editing technologies, to accelerate our understanding of disease biology and the development of precise disease models. Expert opinion: Full understanding and faithful modeling of specific cardiovascular disease is a rate-limiting step for cardiovascular drug discovery. The resurgence of in vivo phenotype screening together with the advancement of systems biology approaches allows for the identification of lead compounds which show efficacy on integrative disease biology in the absence of validated targets. This strategy bypasses current gaps in knowledge of disease biology and paves the way for successful drug discovery and downstream molecular target identification.
我们对心血管疾病病理生理学复杂性的理解仍然非常不完整,这在过去几十年中阻碍了心血管药物的开发。心血管疾病的患病率及其在全球的负担不断增加,需要新的策略来解决疾病生物学和药物发现问题。
本文回顾了使用斑马鱼基于表型的体内筛选进行心血管药物发现的最新历史。强调了使用该模型的基本原理,并说明了疾病建模和高通量筛选领域的初步努力。最后,讨论了体内斑马鱼筛选的优缺点,强调了基因组编辑技术等较新方法,以加速我们对疾病生物学的理解和精确疾病模型的开发。
对特定心血管疾病的充分理解和准确建模是心血管药物发现的限速步骤。体内表型筛选的复兴以及系统生物学方法的进步,使得能够在缺乏验证靶点的情况下,确定对综合疾病生物学有效的先导化合物。这种策略绕过了目前对疾病生物学的认识差距,为成功的药物发现和下游分子靶点识别铺平了道路。