Efects of the calcineurin inhibitory peptide from Paracoccidioides brasiliensis in a platelet-monocyte interaction model

• Grant number: 24/18412-8
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: March 06, 2025
• End date: April 10, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Eugenio Damaceno Hottz
• Grantee: Arthur Fernandes Grasso
• Host Institution: Instituto de Ciências Biológicas (ICB). Universidade Federal de Juiz de Fora (UFJF). Ministério da Educação (Brasil). Juiz de Fora , SP, Brazil

Abstract

Paracoccidioidomycosis (PCM) is an endemic mycosis in Latin America and the main systemic mycosis in Brazil. It is caused by thermodimorphic fungi of the genus Paracoccidioides, which are present in mycelial form in soil and cultures at ambient temperatures, around 25 °C. However, when infecting the human host, these fungi take on the form of pathogenic yeast due to the body temperature of approximately 37 °C, which enables their thermodimorphism. Previous studies conducted by the group demonstrated that calcium-dependent calmodulin calcineurin phosphatase is necessary for the thermodimorphism from mycelium to yeast and for the growth and calcium homeostasis of P. brasiliensis. This serine/threonine phosphatase is a heterodimer composed of a calcium and calmodulin-dependent catalytic subunit (CN-A) and a regulatory subunit (CN-B). Moreover, the carboxy-terminal portion of the CN-A subunit contains an autoinhibitory domain (AID) that directly blocks the catalytic site under basal conditions. Thus, for complete activation of calcineurin, there needs to be an increase in calcium concentration that exceeds its functional threshold, through the binding of Ca²¿ to CN-B and the binding of Ca²¿ to calmodulin, which is also necessary for the activation of the catalytic subunit CN-A, resulting in a functional response. This project aims to define the AID in the C-terminal segment of calcineurin A to model its possible binding to the catalytic domain of calcineurin A from Paracoccidioides, as well as in the same region of human calcineurin A isoforms. The hypothesis is that this peptide may act as a pharmacological tool to inhibit fungal calcineurin if it has low affinity for human enzymes, making it a chemotherapeutic agent against infections caused by fungi of the genus Paracoccidioides or other fungi; or as an immunosuppressant if it has high affinity for human enzymes. (AU)