背景:意外怀孕的高比率和不断增长的世界人口强加了健康,经济,社会,以及对各国的环境威胁。扩大避孕选择,包括男性方法,迫切需要应对这些全球挑战。男性避孕仅限于避孕套和输精管切除术,这对许多夫妇来说是不合适的。因此,新的男性避孕方法可以减少意外怀孕,满足夫妻的避孕需求,并在承担避孕负担方面促进性别平等。在这方面,精子成为按需药物靶标的来源,基于破坏精子运动或受精的非激素男性避孕。
目的:更好地理解控制精子活力的分子可以导致创新的方法,以安全和有效的男性避孕药。这篇综述讨论了男性避孕的精子特异性靶标的尖端知识,专注于那些在精子运动中起关键作用的人。我们还强调了针对精子的男性避孕药物开发中的挑战和机遇。
方法:我们使用以下关键字在PubMed数据库中进行了文献检索:\'精子\',\'精子活力\',\'男性避孕\',和“药物靶标”与该领域的其他相关术语结合使用。直到2023年1月用英语撰写的出版物被考虑。
结果:开发男性避孕非激素策略的努力导致了在精子中特异性表达或富集的候选者的鉴定,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)。这些靶标通常位于精子鞭毛中。通过使用动物模型的遗传或免疫学方法以及由于人类精子缺陷而与男性不育相关的基因突变,证实了它们在精子活力和男性生育能力中不可或缺的作用。通过在临床前试验中鉴定出具有抗精子活性的类似药物的小有机配体,证明了它们的可药用性。
结论:多种精子相关蛋白作为精子运动的关键调节因子,为男性避孕提供令人信服的药物候选药物。然而,没有药物达到临床发展阶段。一个原因是将临床前和药物发现发现转化为适合临床开发的药物样候选物的进展缓慢。因此,学术界之间的密切合作,私营部门,政府,和监管机构将是至关重要的结合专业知识的男性避孕药的发展靶向精子功能通过(一)改善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,功效,和可逆性评估,(iii)为临床试验和监管评估建立严格的指南和终点,从而允许他们在人类身上进行测试。
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.
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.
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.
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.
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.