期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：28
DOI：10.1073/pnas.2026403118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Due to undesirable side effects and other risk factors of current hormonal contraceptives, the world has increasing demand for novel nonsteroidal contraceptives. Unfortunately, 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. In addition, 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.
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.
