Abstract
A significant unmet need for new contraceptive options for both women and men remains due to side-effect profiles, medical concerns, and the inconvenience of many currently available contraceptive products. Unfortunately, the development of novel nonsteroidal female contraceptive medicine has been stalled in the last couple of decades due to the lack of effective screening platforms. Drosophila utilizes conserved signaling pathways for follicle rupture, a final step in ovulation that is essential for female reproduction. Therefore, we explored the potential to use Drosophila as a model to screen compounds that could inhibit follicle rupture and be nonsteroidal contraceptive candidates. Using our ex vivo follicle rupture assay, we screened 1,172 Food and Drug Administration (FDA)-approved drugs and identified six drugs that could inhibit Drosophila follicle rupture in a dose-dependent manner. In addition, we characterized the molecular actions of these drugs in the inhibition of adrenergic signaling and follicle rupture. Furthermore, we validated that three of the four drugs consistently inhibited mouse follicle rupture in vitro and that two of them did not affect progesterone production. Finally, we showed that chlorpromazine, one of the candidate drugs, can significantly inhibit mouse follicle rupture in vivo. Our work suggests that Drosophila ovulation is a valuable platform for identifying lead compounds for nonsteroidal contraceptive development and highlights the potential of these FDA-approved drugs as novel nonsteroidal contraceptive agents.
Highlights
Hormonal contraceptive methods are the most common form of birth control among women of childbearing age globally
Our work suggests that Drosophila ovulation is a valuable platform for identifying lead compounds for nonsteroidal contraceptive development and highlights the potential of these Food and Drug Administration (FDA)-approved drugs as novel nonsteroidal contraceptive agents
We selected an FDA-approved drug library from Selleckchem, which contains 1,172 FDA-approved drugs that target a variety of molecules including G protein–coupled receptors (GPCRs), non-GPCR membrane receptors, cytosolic and nuclear receptors, and various enzymes, including kinases
Summary
Hormonal contraceptive methods are the most common form of birth control among women of childbearing age globally. The development of nonsteroidal contraceptives for women is completely stalled due to little investment from big pharmaceutical companies in this field and lack of effective screening platforms In this manuscript, we describe a phenotypic screening platform utilizing a Drosophila ovulation assay to identify lead compounds that can efficiently inhibit follicle rupture, a final step of releasing mature oocytes during ovulation. We demonstrate that lead compounds identified from Drosophila ovulation could inhibit follicle rupture in mice and have great potential to become nonsteroidal contraceptives for women. Using an in vitro three-dimensional (3D) mouse follicle maturation and ovulation assay [33, 34], we demonstrated that three of the four compounds identified as inhibitors in our Drosophila model could effectively inhibit human chorionic gonadotropin (hCG)–induced mouse follicle rupture as well. A combination of Drosophila and mouse follicle rupture assays is an efficient way to identify small-molecule ovulation inhibitors that could lead to novel nonsteroidal contraceptive development
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