Analysis of the bioportide Modified Stop Sperm 1 (MSS1) on mouse sperm motility

• Grant number: 24/16122-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Erick José Ramo da Silva
• Grantee: Lucas Kenji Kouuti
• 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
• Associated scholarship(s): 25/04498-0 - Effect of the bioportide Modified Stop Sperm 1 (MSS1) on human sperm motility: a pharmacodynamic study, BE.EP.IC

Abstract

Unintended pregnancies correspond to 50% of pregnancies worldwide, leading to health, social, and economic problems for women and their families. Expanding access to contraceptive options is a key strategy to reduce the number of unplanned pregnancies and a goal of the UN's 2030 Agenda for Sustainable Development. Almost 30% of couples rely upon male contraceptive methods, which are currently limited to condoms and vasectomy. This scenario underscores the unmet need for novel male contraceptive methods, which become essential to foster familiar planning and gender equity in birth control. The spermatozoon stands out in the screening for novel pharmacological targets for non-hormonal male contraception, as it expresses a number of specific proteins with crucial roles in fertility and susceptibility to modulation by ligands. Exploring sperm-associated proteins that fit this profile, we highlight the protein phosphatase 1 gamma 2 (PP1¿2). PP1¿2 is specifically expressed in spermatozoa, where it catalyzes the dephosphorylation of serine/threonine residues of target proteins. PP1¿2 activity is inversely associated with sperm motility and post-testicular maturation, being active in immotile and immature spermatozoa located in the caput epididymis but inactive in motile and mature spermatozoa stored in the cauda epididymis until ejaculation. Previous studies aiming to explore the interaction with PP1¿2 from a male contraceptive perspective led to the synthesis of the bioportide Modified Stop Sperm 1 (MSS1), a sperm-penetrating molecule that binds to PP1¿2 with high affinity and selectivity. The bioportide MSS1 keeps PP1¿2 active, resulting in the inhibition of human and bovine sperm motility in vitro. Despite these advances, the preclinical evaluation is still necessary to determine the efficacy and safety of the bioportide MSS1 and, thus, its potential as a novel investigational contraceptive drug. In this project, we aim to investigate the effect of bioportide MSS1 on mouse sperm motility. For that, we will evaluate the motility and viability of (i) isolated spermatozoa from untreated mice exposed to increasing concentrations of MSS1 (in vitro study), and (ii) isolated spermatozoa from treated mice with increasing doses of MSS1 (in vivo study). This project will be the first to evaluate the preclinical efficacy and safety of the bioportide MSS1, aiming to demonstrate its therapeutic potential as a male contraceptive.