Effect of the bioportide Modified Stop Sperm 1 (MSS1) on human sperm motility: a pharmacodynamic study

• Grant number: 25/04498-0
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: June 26, 2025
• End date: October 25, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Erick José Ramo da Silva
• Grantee: Lucas Kenji Kouuti
• Supervisor: Margarida Sancio da Cruz Fardilha
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Institution abroad: Universidade de Aveiro (UA), Portugal
• Associated to the scholarship: 24/16122-2 - Analysis of the bioportide Modified Stop Sperm 1 (MSS1) on mouse sperm motility, BP.IC

Abstract

The sperm proteome contains exclusively expressed proteins with essential roles in male fertility, which may have therapeutic applications in male contraception. Among the proteins that fit into this profile, we highlight the protein phosphatase 1 gamma 2 (PP1¿2). PP1¿2 is a sperm-specific isoform of a family of phosphatases that act dephosphorylating serine/threonine residues of target proteins. In mammals, PP1¿2 activity is inversely correlated to sperm motility, being active in immotile and immature spermatozoa found in the caput epididymis but inactive in motile and mature spermatozoa found in cauda epididymis. Studies aiming to explore PP1¿2 as a male contraceptive target led to the rational design of the bioportide Modified Stop Sperm 1 (MSS1), a molecule capable of penetrating spermatozoa and selectively binding to PP1¿2. Acting as a dominant negative, MSS1 blocks PP1¿2 interaction with the sperm-specific protein A-kinase anchoring protein 4 (AKAP4). As a result, PP1¿2 remains active, resulting in sperm immotility. Advancing the development of MSS1 as a male contraceptive drug relies on additional studies to better characterize its efficacy and safety as a spermiostatic molecule. In the current undergraduate research project, the candidate for this scholarship has been investigating the effects of MSS1 using the mouse as an experimental model, showing that MSS1 is a potent inhibitor of sperm motility. In this project, linked to the application of a BEPE-IC scholarship, we propose to evaluate the pharmacodynamic aspects of the bioportide MSS1 in human spermatozoa in vitro. Our objectives are 1) to assess the concentration-response relationship of its spermiostatic activity, determining its potency in vitro; and 2) to investigate whether MSS1 promotes sperm cytotoxicity. To achieve these aims, we will evaluate the motility and viability of human spermatozoa exposed to increasing concentrations of MSS1 in vitro. This proposal benefits from the collaboration of the research group led by Prof. Dr. Margarida Fardilha, University of Aveiro, Portugal, a world-leading scientist in the study of sperm phosphatases and their application in non-hormonal male contraception. This will be the first pharmacodynamic study of MSS1 in human spermatozoa, representing a step forward in its development as a contraceptive molecule (AU)