| Summary: | Sperm motility acquisition and maintenance is a fundamental process for oocyte fertilization and consequently conception. The signaling events underling sperm motility acquisition have been studied for decades. However, many questions are still unanswered. Also, the limited options currently available for male contraception (condom, vasectomy and withdrawal) reflect the necessity of a new group of male contraceptives based on sperm motility modulation. GSK3/PPP1R2/PPP1 signaling pathway is involved in sperm motility acquisition during epididymis transit. The main goal for this work was to deepen the knowledge on the signaling events involved in human sperm motility by focusing on the characterization and modulation of the signaling pathway GSK3/PPP1R2/PPP1. We first designed, synthetized and characterized a disruptive bioportide based on cell penetrating peptide technology. In vitro studies revealed that the disruptive bioportide interferes with PPP1R2/PPP1CC2 interaction and restores PPP1CC2 activity. We also demonstrated that when exposed to the disruptive bioportide, sperm motility is significantly reduced. Aiming to identify sperm protein-protein interactions suitable for pharmacological intervention, we turn our attention to GSK3, a modulator of PPP1R2/PPP1CC2 interactions in sperm. We provide for the first time GSK3 human testis and sperm interactomes. We reported an isoforms specific role for GSK3 in human sperm motility and an in silico analysis revealed GSK3 and GSK3 interactions involved in sperm motility and potential targets for pharmacological intervention. In conclusion, we demonstrated that it is possible to target protein-protein interactions and modulate sperm complexes involved in motility using bioportides. Moreover, we identified new potential protein interactions involved in sperm motility and showed that the development of new type of male contraceptive based on inhibiting sperm motility is now achievable.
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