Dissecting Antimalarial Efficacy of GlaxoSmithKline Compounds Across Parasite cycles and BRET studies into the GPCR-like Protein PvSR1

• Grant number: 24/22379-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Célia Regina da Silva Garcia
• Grantee: Waheed Ahmed
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/08684-7 - Decoding Plasmodium signaling at molecular level as a new tool to the development of new antimalarials, AP.TEM

Abstract

The emergence of resistance to commonly used antimalarial drugs underscores the urgent need for innovative treatment strategies, including extensive compound screening efforts. This study evaluated the antimalarial potential of 30 compounds selected from an initial screening of over 13,000 candidates in the TCAM/GSK antiplasmodial compound library. Eight compounds exhibited potent activity against the Plasmodium falciparum 3D7 strain, with IC50 values ranging from 2.6 nM (Compound 53) to 99.65 nM (Compound 10), all effective at concentrations below 100 nanomolar (nM). Importantly, these active compounds showed no cytotoxicity in HEK 293 cells at the tested concentrations. Utilizing PfGCaMP3 parasites, we observed that some of these compounds induce a rise in intracellular Ca2+. Additionally, the study highlights the transmission-blocking potential of these eight GSK compounds, which demonstrated significant inhibitory effects against mature stage IV/V gametocytes of P. falciparum, showing their potential as transmission-blocking agents. In parallel, our research focused on G protein-coupled receptors (GPCRs) in Plasmodium falciparum, identifying four serpentine receptor-like proteins as potential targets for malaria intervention. Among these, PfSR1 and PfSR10 are expressed during the asexual stage, with PfSR10 forming dimers and enhancing PfSR1 expression. We propose further exploration of PfSR10 through mutational studies to investigate its role in PfSR1 expression, dimerization, and signaling activation in cells expressing PfSR1. Additionally, comparative analysis of the Plasmodium vivax homolog of SR1 will be conducted to uncover potential functional similarities with PfSR1. These findings contribute to the development of novel antimalarial therapeutics and deepen our understanding of key molecular mechanisms in malaria, particularly through the exploitation of Ca2+ signaling pathways and GPCR functions.