Investigating anti-tumor activity of antimicrobial peptides in asymmetric membranes mimicking the membrane of tumor cells.

• Grant number: 25/01025-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2025
• End date: June 30, 2028
• Field of knowledge: Physical Sciences and Mathematics - Physics - Condensed Matter Physics
• Principal Investigator: Thais Azevedo Enoki Liarte
• Grantee: Guilherme Xavier Pinheiro
• Host Institution: Instituto de Física (IF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/04046-4 - Investigating the asymmetry of the plasma membrane: model membranes mimicking healthy and tumor cells, and anti-tumor therapeutic strategies, AP.JP

Abstract

The plasma membrane (PM) comprises a lipid bilayer composed of two leaflets with distinct lipid compositions, commonly described as an asymmetric bilayer. Phosphatidylserine (PS) is a negatively charged lipid retained in the inner leaflet of the PM in healthy cells. Exposing the lipid PS to the exoplasmic leaflet leads to a cascade of events that signal apoptosis. Cancer cells also display PS exposure. The exposed PS could be the main target for therapeutic strategies involving any molecule attracted to PS with a potent anti-tumor effect. For example, many antimicrobial peptides (AMPs) have mighty anti-cancer activity. These cationic peptides preferentially interact with anionic phospholipids (e.g., phosphatidylglycerol) in the outer leaflet of bacterial membranes. Similar selectivity occurs between these peptides and anionic lipids on the outer leaflet of tumor cells. We propose to study the interaction between AMPs and model membranes mimicking the plasma membrane of healthy and tumor cells. We aim to incorporate the bilayer asymmetry in our models and characterize the main differences in the peptide mechanism acting in symmetric and asymmetric bilayers. We propose to evaluate changes in bilayer structure, leakage of vesicle content, and modifications in mechanical properties, such as changes in bending moduli. We plan to investigate models with the coexistence of liquid phases - liquid-disordered (Ld) and liquid-ordered phases (Lo), mimicking "lipid rafts," and investigate peptide partitioning between these phases and changes regarding lipid partitioning and interactions controlling domain sizes and morphologies. We are also interested in evaluating the changes in the inter-leaflet coupling caused by the peptide in healthy and tumor membrane models. We aim to use the peptides gramicidin, melittin, and PGLa. These peptides have been proven to interact with the membrane and negatively charged lipids. By clarifying the peptide mechanism in these models, we may identify optimal conditions that enhance peptide targeting into tumor cells and improve its efficacy in killing them, potentially leading to improved cancer treatments.