BACKGROUND The high rates of unintended pregnancy and the ever-growing world population impose health, economic, social, and environmental threats to countries. Expanding contraceptive options, including male methods, are urgently needed to tackle these global challenges. Male contraception is limited to condoms and vasectomy, which are unsuitable for many couples. Thus, novel male contraceptive methods may reduce unintended pregnancies, meet the contraceptive needs of couples, and foster gender equality in carrying the contraceptive burden. In this regard, the spermatozoon emerges as a source of druggable targets for on-demand, non-hormonal male contraception based on disrupting sperm motility or fertilization. OBJECTIVE AND RATIONALE A better understanding of the molecules governing sperm motility can lead to innovative approaches toward safe and effective male contraceptives. This review discusses cutting-edge knowledge on sperm-specific targets for male contraception, focusing on those with crucial roles in sperm motility. We also highlight challenges and opportunities in male contraceptive drug development targeting spermatozoa. SEARCH METHODS We conducted a literature search in the PubMed database using the following keywords: ‘spermatozoa’, ‘sperm motility’, ‘male contraception’, and ‘drug targets’ in combination with other related terms to the field. Publications until January 2023 written in English were considered. OUTCOMES Efforts for developing non-hormonal strategies for male contraception resulted in the identification of candidates specifically expressed or enriched in spermatozoa, including enzymes (PP1γ2, GAPDHS, and sAC), ion channels (CatSper and KSper), transmembrane transporters (sNHE, SLC26A8, and ATP1A4), and surface proteins (EPPIN). These targets are usually located in the sperm flagellum. Their indispensable roles in sperm motility and male fertility were confirmed by genetic or immunological approaches using animal models and gene mutations associated with male infertility due to sperm defects in humans. Their druggability was demonstrated by the identification of drug-like small organic ligands displaying spermiostatic activity in preclinical trials. WIDER IMPLICATIONS A wide range of sperm-associated proteins has arisen as key regulators of sperm motility, providing compelling druggable candidates for male contraception. Nevertheless, no pharmacological agent has reached clinical developmental stages. One reason is the slow progress in translating the preclinical and drug discovery findings into a drug-like candidate adequate for clinical development. Thus, intense collaboration among academia, private sectors, governments, and regulatory agencies will be crucial to combine expertise for the development of male contraceptives targeting sperm function by (i) improving target structural characterization and the design of highly selective ligands, (ii) conducting long-term preclinical safety, efficacy, and reversibility evaluation, and (iii) establishing rigorous guidelines and endpoints for clinical trials and regulatory evaluation, thus allowing their testing in humans.

中文翻译：

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针对精子活力的非激素男性避孕药的进展

背景技术意外怀孕的高发生率和不断增长的世界人口给各国带来了健康、经济、社会和环境威胁。为了应对这些全球挑战，迫切需要扩大避孕选择，包括男性避孕方法。男性避孕仅限于避孕套和输精管结扎术，这对许多夫妇来说并不适合。因此，新型男性避孕方法可以减少意外怀孕，满足夫妇的避孕需求，并促进承担避孕负担的性别平等。在这方面，精子成为基于扰乱精子活力或受精的按需、非激素男性避孕的可药物靶点的来源。目标和基本原理更好地了解控制精子活力的分子可以带来安全有效的男性避孕药的创新方法。这篇综述讨论了男性避孕的精子特异性靶点的前沿知识，重点关注那些在精子活力中发挥关键作用的靶点。我们还强调了针对精子的男性避孕药物开发的挑战和机遇。检索方法我们使用以下关键词在 PubMed 数据库中进行文献检索：“精子”、“精子活力”、“男性避孕”和“药物靶标”，并结合该领域的其他相关术语。考虑到 2023 年 1 月之前以英文撰写的出版物。结果 开发男性避孕非激素策略的努力导致了精子中特异性表达或富集的候选物的鉴定，包括酶（PP1γ2、GAPDHS 和 sAC）、离子通道（CatSper 和 KSper）、跨膜转运蛋白（sNHE、SLC26A8、和 ATP1A4) 和表面蛋白 (EPPIN)。这些目标通常位于精子鞭毛中。它们在精子活力和男性生育能力中不可或缺的作用已通过使用动物模型的遗传或免疫学方法以及与人类精子缺陷导致的男性不育相关的基因突变得到证实。通过在临床前试验中鉴定出具有抑精活性的类药物小有机配体，证明了它们的成药性。更广泛的影响 作为精子活力的关键调节因子，多种精子相关蛋白已经出现，为男性避孕提供了令人信服的药物候选者。然而，尚无药物制剂达到临床开发阶段。原因之一是将临床前和药物发现结果转化为适合临床开发的类药物候选物方面进展缓慢。因此，学术界、私营部门、政府和监管机构之间的密切合作对于结合专业知识来开发针对精子功能的男性避孕药至关重要，方法是：（i）改进目标结构表征和高选择性配体的设计，（ii）进行长期临床前安全性、有效性、