Determining the mode of action of peptide-like molecules with pronounced antiplasmodial activity against Plasmodium falciparum resistant strains

• Grant number: 23/10879-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: February 01, 2024
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Igor Mota Rodrigues de Moura
• Supervisor: David Fidock
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Institution abroad: Columbia University in the City of New York, United States
• Associated to the scholarship: 21/03977-1 - Discovery of inhibitors from Brazilian Savana plants as lead compound candidates for Malaria, BP.DR

Abstract

Malaria remains a significant global public health challenge, affecting millions of individuals each year and placing a heavy burden on healthcare systems, especially in regions with high transmission rates. Over the years, the emergence and spread of resistant parasites have posed a serious threat to malaria treatment. This has led to a pressing need for the validation of new molecular targets and the discovery of new antimalarial candidates. Peptide-based inhibitors have emerged as an attractive alternative due to their antimicrobial properties, anti-tumor effects, and antiplasmodial activity. We have been exploring the potential of tri- and dipeptide-like derivatives as new P. falciparum inhibitors. The most promising compound, Neq1153, has shown inhibitory activity in the sub-micromolar range against a panel of sensitive and resistant P. falciparum strains. Given its characteristics as a small peptide-like compound, it is likely that Neq1153 acts as a protease inhibitor by interfering with the digestive vacuole. However, we currently lack solid evidence regarding the underlying mechanism of action for the inhibitory activity of Neq1153. Genetic engineering, particularly the CRISPR/Cas9 system, has revolutionized gene function studies, enabling researchers to investigate potential drug targets and vaccine antigens in the P. falciparum parasite. Thus, in this proposal we aimed at investigating the mode of action and mechanism of resistance of Neq1153 using a combination of cutting-edge technologies including CRISPR/Cas9, generation of resistant parasites, whole-genome sequencing, bioinformatics, and cell-based assays. The investigation will be performed under the supervision of Prof. David A. Fidock from the Columbia University Irving Medical Center (CUIMC), New York, USA. His group has been leading the use of genetic tools to understand parasite biology and develop new drugs, drugs with new modes of action, and new druggable proteins and pathways.The coordinated application of these techniques and experiments will pave the way towards the understanding of Neq1153's antiplasmodial properties and unraveling its mode of action within the parasite. The findings may also extend our knowledge of malaria biology and resistance mechanisms, opening new avenues for therapeutic development. Moreover, the knowledge and skills gained through this internship abroad will ripple through various research areas, strengthening existing initiatives, and fostering a new collaborative initiative between Brazil and USA. (AU)