Determining the mode of action of synthetic guanidine derivatives with antiplasmodial activity against Plasmodium falciparum

• Grant number: 25/02202-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: August 01, 2025
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Giovana Rossi Mendes
• Supervisor: Matthias Rottmann
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Institution abroad: Swiss Tropical and Public Health Institute, Switzerland
• Associated to the scholarship: 22/01063-5 - Characterization of the antiplasmodial activity of natural products isolated from fungal metabolites as lead candidates for Malaria, BP.DD

Abstract

Malaria is a disease caused by pathogenic protozoa Plasmodium spp., with a significant global impact on human health. The increasing resistance of P. falciparum strains, the causative agent of the most severe form of the disease, to commercial drugs like chloroquine and artemisinin highlights the urgent need to discover new antimalarial candidates.Batzelladines are marine guanidine alkaloids that exhibit potent antiparasitic activity. We have been investigating the parasitological profile of batzelladines F and L (IC503D7 = 0.13 ¿M and IC503D7 = 0.4 ¿M, respectively), and the results provide a strong rationale for developing guanidine alkaloid derivatives as lead candidates for malaria treatment. In this sense, we screened 234 synthetic guanidine derivatives as new P. falciparum inhibitors, and 5% of the derivatives (12 compounds) showed high potency against the parasite, with IC¿¿ values below 0.1 µM, representing a notable improvement in antiplasmodial activity compared to batzelladines.Understanding the mode of action (MoA) of new antimalarial compounds is crucial for addressing the ongoing global challenge posed by malaria. Thus, this project focuses on investigating the mode of action of synthetic guanidine derivatives by employing assays such as Parasite Reduction Ratio (PRR) Assay Version 2, iSPP in P. falciparum, the P. falciparum humanized NOD-scid IL2Rnull mouse model, and others. These methodologies provide a robust framework for elucidating the compounds´ MoA. The investigation will be performed under the supervision of Dr. Matthias Rottmann and Prof. Dr. Pascal Mäser from the Swiss Tropical and Public Health Institute (Swiss-TPH), Allschwil, Switzerland. The Parasite Chemotherapy Unit (PCU) at the Swiss TPH has been a global leader in assay development and the drug discovery process for new antimalarial treatments. By integrating these techniques and experiments, we aim to uncover the antiplasmodial effects of synthetic guanidine derivatives and reveal their specific mode of action within the parasite. The results of this study should not only enhance our understanding of malaria biology and mechanisms of action but also pave the way for the development of novel therapeutic strategies. Additionally, the knowledge and expertise gained during this international internship will have a far-reaching impact, enriching ongoing research efforts and promoting future collaborations between Brazil and Switzerland. (AU)