Compounds Reducing Human Sperm Motility as Potential Nonhormonal Contraceptives Identified Using a High-Throughput Phenotypic Screening Platform

Sep 29, 2026

Phenotypic screening was used to discover potential nonhormonal contraceptive compounds that selectively reduce human sperm motility. Nine compound libraries totaling 88,773 compounds were tested with an automated robotic in-house platform, quantifying motility in compound-pretreated sperm samples. Nine chemical series emerged and were advanced through hit-expansion studies, emphasizing low cytotoxicity in somatic HepG2 cells. No clinically progressable leads were found, but tool compounds and process insights supported future optimization for improved starting points.

LanguageEnglish

CategoryResearch & Report

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Pages14

Reading Time35 min

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Abstract

Introduction

This article is licensed under CC-BY 4.0 [http://pubs.acs.org/journal/acsodf](http://pubs.acs.org/journal/acsodf) Article Compounds Reducing Human Sperm Motility as Potential Nonhormonal Contraceptives Identified Using a High-Throughput Phenotypic Screening Platform Anthony Richardson, * Franz S. Gruber, David P. Day, Darren Edwards, Irene Georgiou, Zoe C. Johnston, Halimatu Joji, Sarah Martins da Silva, Rachel Myles, Neil R. Norcross, Kevin D. Read, Jason R. Swedlow, Caroline Wilson, Christopher L. R. Barratt, and Ian H. Gilbert Cite This: ACS Omega 2025, 10, 59121−59134 Read Online | | | | | | | | --- | --- | --- | --- | --- | --- | | ACCESS | Metrics & More | | Article Recommendations | | *sı Supporting Information | ABSTRACT: In this article, we detail our latest findings toward developing a diversified series of potential nonhormonal contraceptive compounds using a phenotypic screening approach against human sperm. Phenotypic screening of nine compound libraries (88,773 compounds in total) was conducted using an in-house automated robotic screening platform, allowing quantification of sperm motility in samples pretreated with the compounds. From these screens, 9 chemical series were identified and investigated in hit expansion programs, with a particular focus on identifying chemical matter that selectively reduces sperm motility without any significant cytotoxicity in somatic cells (HepG2 cells). While there were no clinically progressable leads identified, the study did identify some useful tool compounds for research into the fundamental biology underpinning nonhormonal contraceptive discovery, and a lot was learned about the screening technology, which sets us up for future screening to identify and develop better chemical starting points. ■ INTRODUCTION The large number of unwanted pregnancies worldwide (121 million per year 1) and the associated impact on society are sentinel markers of the need for new methods of contraception. Current birth control options are limited to barrierbased methods, surgical intervention, intrauterine devices, orthe female contraceptive pill, which was developed over 60 years ago. As revolutionary as the female contraceptive pill has been, it does cause severe and potentially life-threatening side effects in some women and has compliance issues due to the strict dosing regimen required.1 Most of these issues stem from the fact that the contraceptive pill is a hormonal contraceptive with systemic exposure and, therefore, effects throughout the body. In the case of men, the only contraceptive methods are condoms or vasectomy. Therefore, it would be extremely beneficial to develop nonhormonal contraceptives for either women or men. One option to achieve this is to develop smallmolecule drugs that impact sperm function. There is clinical data that can be used to inform the effects of sperm dysfunction on human fertility, which makes this a very attractive approach.2 There are known biological targets that impact sperm function, some of which are being investigated for nonhormonal contraceptives, such as soluble adenylyl cyclase (sAC),3 CatSper,4,5 and cyclin-dependent kinase-2 (CDK2).6 While a significant amount of work has focused on these targets, no clinical candidates have been developed based on these mechanisms. The first clinical trial of a nonhormonal male contraceptive commenced in December 2023, with YCT- | Received: August 18, 2025
Revised: September 26, 2025
Accepted: November 18, 2025
Published: November 27, 2025 | | | --- | --- | © 2025 The Authors. Published by American Chemical Society 59121 [https://doi.org/10.1021/acsomega.5c08336](https://doi.org/10.1021/acsomega.5c08336) ACS Omega 2025, 10, 59121−59134 Figure 1. Overview of the screening platform and screening efforts. (A) Donated human sperm samples were prepared using standard differential gradient centrifugation to enrich for high-quality sperm cells used (in 80

FAQs

How was human sperm motility measured in the screening campaign?

Sperm samples were pretreated with compounds and screened using an in-house automated robotic platform. Sperm motility was quantified from assay-ready plates in a 384-well format.

What size and scope of chemical libraries were screened?

Nine compound libraries comprising 88,773 compounds were screened, followed by hit expansion of nine identified chemical series.

Were any clinically progressable leads identified?

No clinically progressable leads were identified. However, the study reported useful tool compounds and learnings about the screening technology for future efforts.

Sep 29, 2026

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