National Phenotypic Screening Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
Reproductive and Developmental Biology, Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
Elife. 2020 Jan 28;9:e51739. doi: 10.7554/eLife.51739.
There is an urgent need to develop new methods for male contraception, however a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system. To address this deficit, we developed a fully-automated robotic screening platform that provided quantitative evaluation of compound activity against two key attributes of human sperm function: motility and acrosome reaction. In order to accelerate contraceptive development, we screened the comprehensive collection of 12,000 molecules that make up the ReFRAME repurposing library, comprising nearly all the small molecules that have been approved or have undergone clinical development, or have significant preclinical profiling. We identified several compounds that potently inhibit motility representing either novel drug candidates or routes to target identification. This platform will now allow for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.
非常有必要开发新的男性避孕药，但药物研发的一个主要障碍是缺乏经过验证的靶点和有效的高通量表型筛选系统。为了解决这一不足，我们开发了一个全自动的机器人筛选平台，对化合物在两个关键的人类精子功能属性上的活性进行了定量评估：运动能力和顶体反应。为了加速避孕药的研发，我们筛选了包含 12000 种小分子的 ReFRAME 再利用文库，其中几乎包括所有已批准或已进行临床开发的小分子，或具有重要的临床前特征。我们发现了几种能有效抑制运动能力的化合物，它们代表了新的候选药物或靶标识别途径。这个平台现在将允许进行重大的药物发现计划，以解决避孕产品组合中的关键差距，并揭示新的人类精子生物学。
