Developing EPPIN-binding peptides with spermostatic activity for male contraception

• Grant number: 25/02448-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2025
• End date: March 31, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Erick José Ramo da Silva
• Grantee: Noemia Aparecida Partelli Mariani
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated research grant: 21/06718-7 - Translational studies on the sperm-binding protein EPPIN as a male contraceptive drug target, AP.JP2

Abstract

Although male contraceptive options are limited to condoms and vasectomy, almost 30% of couples rely on them as their main contraceptive choice. New male contraceptives are under development to fulfill this unmet need, profoundly impacting family planning and health. EPPIN (epididymal protease inhibitor) is a sperm protein with crucial roles in male fertility. EPPIN works as a central hub for a protein complex on the sperm surface that inhibits sperm motility upon semenogelin-1 (SEMG1) binding during ejaculation. Due to its druggable properties, the SEMG1-binding surface on EPPIN is a promising target for non-hormonal male contraceptive development targeting spermatozoa. Peptide-based compounds targeting protein-protein interactions in spermatozoa represent an emerging and innovative approach in male contraceptive drug discovery. We aim to generate a small library of EPPIN-binding peptides targeting EPPIN protein-protein interaction surface with high affinity as an approach for the rational design of novel ligands with spermostatic activity. We will design a series of peptides (5-15 amino acid residues) targeting the EPPIN sequence involved in its interaction with SEMG1. We will generate a series of peptides (10-20 amino acid residues) targeting the EPPIN sequence involved in its interaction with SEMG1 and containing flanking regions yielding high stability in body fluids and water solubility using a high-throughput microwave-assisted solid-phase peptide synthesis platform. Upon purification and sequencing by HPLC and mass spectrometry, we will determine peptide binding to EPPIN using AlphaScreen competition assays. High-affinity lead peptides will be screened for their ability to inhibit mouse and human sperm motility. We expect to produce the first generation of EPPIN-based peptides, which will result in a novel class of EPPIN ligands with pharmacological applications for male contraception.