INHIBITION OF JUNO-IZUMO1 INTERACTION TO PREVENT FERTILIZATION

Human fertilization is the fundamental process for producing new life, and its regulation has become a great challenge for scientists since the beginning of the drug discovery era. Up to date, only hormonal oral contraceptives are available despite efforts to develop non-hormonal therapeutics. The latter may have potential advantages, e.g. an absence of side effects and a convenient, on-demand use. Difficulties to design such contraceptive are due to the complexity of pathways. The search for a proper target from the myriad of proteins engaged in fertilization reached a first breakthrough in 2014, when the interaction between two proteins – IZUMO1, a sperm membrane protein, and its counterpart oocyte receptor JUNO – was reported to be essential for sperm-oocyte fusion, a critical step of fertilization. Then, in 2016, two research groups published X-ray structures of IZUMO1-JUNO complexes. We hypothesize that blocking the IZUMO1-JUNO interaction by a small molecule could lead to non-hormonal contraceptives. No ligands disrupting that interaction have been reported as yet. Starting with JUNO, we searched the interface of the complex (Ala scan) to identify "hot spots" and performed docking of two virtual libraries (altogether ~1.4 million commercially available, drug-like small molecules) using Schrodinger software. An initial group of 32 top-scored molecules was sent to in vitro experiments. Using IVF technique we found 2 small molecules that inhibited fertilization 100% in concentration 100uM. Those molecules will be used for in vivo tests with mice as well as in virto penetration assay using human sperm and hamster eggs.