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

Malaria remains a significant global public health challenge, affecting millions of individuals each year and straining health systems, especially in regions with high transmission rates. Over the years, the emergence and spread of resistant parasites have posed a serious threat to the treatment of malaria. This has led to an urgent need for validation of new molecular targets and discovery of new antimalarial candidates. Peptide-based inhibitors have emerged as an attractive alternative due to their antimicrobial properties, antitumor effects and antiplasmodial activity. The potential of tri- and dipeptide derivatives as novel inhibitors of P. falciparum has been explored. The most promising compound, Neq1153, demonstrated inhibitory activity in the submicromolar range against a panel of sensitive and resistant strains of P. falciparum. Given its characteristics as a small peptide-like compound, it is likely that Neq1153 acts as a protease inhibitor, interfering with the digestive vacuole. However, currently there is lack solid evidence regarding the underlying mechanism of Neq1153’s inhibitory activity. Genetic engineering, particularly the CRISPR/Cas9 system, has revolutionized gene function studies, allowing researchers to investigate potential drug targets and vaccine antigens. in the parasite P. falciparum. The investigation will be carried out under the supervision of Prof. David A. Fidock of Columbia University Irving Medical Center (CUIMC), New York, USA. His group has led the use of genetic tools to understand the biology of the parasite and develop new drugs, with new modes of action, proteins and pharmacologically viable pathways. The coordinated application of these techniques and experiments will pave the way for understanding the antiplasmodial properties of Neq1153 and to unravel its mode of action within the parasite. The results could also expand our knowledge of malaria biology and resistance mechanisms, opening new opportunities for therapeutic development. Furthermore, the knowledge and skills acquired through this internship abroad will have effects in several areas of research, strengthening existing initiatives and promoting new collaboration between Brazil and the USA.

Project details

Basic Science
Drug-based Strategies

Feb 2024 — Jan 2025

Brazil