A Primary Evaluation of Potential Small-Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, a Novel Drug Target in Female Infertility Treatment

Abstract

Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin-B and the cortical granule-based proteinase ovastacin to be a novel key mechanism in the regulation of fertilization. Upon sperm–egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness, and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this process is controlled by fetuin-B, an endogenous ovastacin inhibitor. Here we aimed to discover small-molecule inhibitors of ovastacin that could mimic the effect of fetuin-B. These compounds could be useful lead structures for the development of specific ovastacin inhibitors that can be used in infertility treatment or in vitro fertilization.