Abstract
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.
Highlights
An effective and comprehensive family planning strategy is fundamental to delivery on the United Nations 17 Sustainable Development Goals (Starbird et al, 2016; Goodkind et al, 2018), the current contraceptive portfolio is suboptimal
There is an urgent need to develop new methods for male contraception, a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system
The kinetics show good agreement with clinical systems (Figure 1— figure supplement 1C) and a comparable distribution was observed between experimental days, plates and positions (Figure 1—figure supplement 2) with any small differences between days stemming from donor pool variance
Summary
An effective and comprehensive family planning strategy is fundamental to delivery on the United Nations 17 Sustainable Development Goals (Starbird et al, 2016; Goodkind et al, 2018), the current contraceptive portfolio is suboptimal. The platform was used to identify motility inhibitors from a unique 12,000 molecule ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library, which represents the most comprehensive collection of drugs available, as it contains most the small molecules that have achieved regulatory approval and others that have undergone varying degrees of clinical development or have had significant preclinical profiling (Janes et al, 2018) This advance opens up the possibility of accelerated male contraceptive development by allowing drug repurposing, target identification as well as screening of chemical diversity libraries for novel medicinal chemistry start points
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