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

• Published in: ChemMedChem 2020-08, Vol.15 (16), p.1499-1504
• Main Authors: Körschgen, Hagen, Jäger, Christian, Tan, Kathrin, Buchholz, Mirko, Stöcker, Walter, Ramsbeck, Daniel
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Amines - pharmacology; Animals; Astacin; astacins; Biocatalysis; Communication; Communications; Dose-Response Relationship, Drug; Female; hydroxamate; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; In vitro fertilization; In vitro methods and tests; Infertility; Infertility, Female - drug therapy; Infertility, Female - metabolism; Inhibitors; Medical treatment; Metalloproteases - antagonists & inhibitors; Metalloproteases - metabolism; Metalloproteinase; metzincins; Mice; Models, Molecular; Molecular Structure; ovastacin; Proteinase; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Sperm; Structure-Activity Relationship; Therapeutic targets; Zona pellucida
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202000397

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 Paving the way for novel infertility treatment: We report the first small‐molecule inhibitors of the astacin proteinase ovastacin. A focused screening of tertiary amine–based hydroxamates revealed compounds with activity in the nanomolar range that could serve as tool or lead compounds for the development of small‐molecule infertility treatment or as supplement for successful in vitro fertilization.