Pyrrole-Based, Macrocyclic, Small-Molecule Inhibitors Targeting Oocyte Maturation

Polo-like kinase 1 (PLK1) plays crucial roles in various stages of oocyte maturation. Recently, we reported that the peptidomimetic AB103-8 that targets polo box domain (PBD) of PLK1 affected oocyte meiotic maturation and meiosis resumption. However, to overcome the peptidic drawbacks, we designed and synthesized a series of pyrrole-based small-molecule inhibitors and screened against porcine oocyte maturation rates. Among them, compound 4 showed the highest inhibitory activity with enhanced inhibition against the embryos blastocyst formation. Furthermore, the addition of this compound to culture medium efficiently blocked the maturation of porcine and mouse oocytes, indicating that the lead compound could penetrate zona pellucida and cell membrane. To prove the PLK1 inhibition, we investigated the compound 4 treated mouse oocytes which confirmed the PLK1 inhibition by showing impaired spindle formation. Finally, molecular modeling studies with PLK1 PBD also confirmed the presence of significant interactions between compound 4 and Plk1 PBD binding pockets, including phosphate, tyrosine-rich and pyrrolidine binding pockets. Collectively, these results suggest that the macrocyclic compound 4 may serve as a promising template for the development of novel contraceptive agents.