3D structure of key protein could advance development of hormone-free male contraceptive pill

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Melbourne-based scientists behind the development of a hormone-free, reversible male contraceptive pill have, for the first time, solved the molecular structure of the discovery program's primary therapeutic target, significantly increasing the chance of the drug becoming a reality.

In previous studies, the Monash University team have shown that male infertility can be genetically achieved by simultaneously deleting two proteins that trigger the transport of sperm—α1A-adrenergic receptor and P2X1-purinergic receptor (P2X1)—but without affecting the long-term viability of sperm or sexual and general health.

However, until now, the lack of knowledge around the chemical biology of P2X1 has meant it has been like "throwing darts at a dartboard hoping for success" according to one of the new study's senior authors, Dr. Sab Ventura.

Published in Nature Communications, the team used cryo‐electron microscopy (cryo‐EM) to determine the 3D structure of P2X1, allowing for a more focused and accurate structure-based drug design program.

Dr. Ventura, from the Monash Institute of Pharmaceutical Sciences (MIPS), has been leading the male contraceptive program for more than two decades, and said the team is excited to overcome the main stumbling block that has so far hindered them from progressing the drug discovery program to the next stage in its journey.

"Our primary goal is to develop a male contraceptive pill that is not only hormone-free but also bypasses side effects such as long-term irreversible impacts on fertility and, thus, making it suitable for young men seeking contraceptive options," Dr. Ventura said.

"While there are numerous drugs in clinical use that target the α1A-adrenergic receptor, designing drugs to target P2X1 has been a lot more challenging. Now we know what our therapeutic target looks like, we can generate drugs that can bind to it appropriately, which totally changes the game."

Senior author Associate Professor David Thal, also from MIPS, said solving the molecular structure of P2X1 is an important advancement for the research group.

"Cryo-EM has revolutionized drug discovery by enabling researchers to determine the 3D structure of molecules previously too difficult to observe. By tapping into this state-of-the-art technology, we've been able to describe the first ever high-resolution structure of P2X1, opening up an exciting new suite of opportunities for developing drugs to target this receptor," Associate Professor Thal said.

At the moment, the options for male contraception include only condoms and vasectomy, with the burden of preventing pregnancy largely and unevenly falling on women.

"Unfortunately, there has been a widespread perception that birth control is a women's problem rather than a men's problem—we hope to change that," said Dr. Ventura.

More information: Felix M. Bennetts et al, Structural insights into the human P2X1 receptor and ligand interactions, Nature Communications (2024). DOI: 10.1038/s41467-024-52776-7

Journal information: Nature Communications

Provided by Monash University