A Computational Strategy for Identifying Self-Assembling Food-Derived Molecules for Antiparasitic Nanotherapy

Area of Science:

• Nanotechnology
• Natural Products Chemistry
• Parasitology

Background:

• Designing carrier-free nanodrugs and understanding their self-assembly mechanisms are significant challenges in drug development.
• Existing nanodrugs often require complex carriers, limiting their application and bioavailability.

Purpose of the Study:

• To identify self-assembling bioactive molecular pairs from food-derived compounds using an integrated screening approach.
• To develop and characterize novel, stable, carrier-free nanoparticles with enhanced therapeutic properties.

Main Methods:

• Utilized a workflow combining 2D/3D molecular screening and SHAP-assisted analysis to identify self-assembling pairs.
• Synthesized and characterized ursolic acid and 18β-glycyrrhetinic acid nanoparticles (UA-18βGA NPs) using spectroscopic techniques.
• Employed density functional theory (DFT) calculations and molecular dynamics (MD) simulations to elucidate intermolecular interactions and nanoparticle structure.
• Evaluated antiparasitic activity against Ichthyophthirius multifiliis in vitro and in vivo (zebrafish model).
• Assessed therapeutic efficacy in a murine model of experimental cerebral malaria.

Main Results:

• Identified ursolic acid and 18β-glycyrrhetinic acid as self-assembling compounds forming stable UA-18βGA NPs.
• UA-18βGA NPs demonstrated reduced cytotoxicity and synergistic antiparasitic activity compared to individual components.
• Nanoparticles induced parasite apoptosis via Erk1/Akt signaling and modulated host immune responses in zebrafish.
• In a malaria model, UA-18βGA NPs improved therapeutic outcomes, reduced neuroinflammation, and mitigated blood-brain barrier leakage.

Conclusions:

• UA-18βGA NPs represent a promising natural product-based nanoformulation for antiparasitic therapy.
• The integrated screening strategy is effective for discovering self-assembling bioactive molecular combinations.
• Carrier-free nanoparticles offer advantages in terms of reduced toxicity and enhanced efficacy for treating parasitic infections.