Identification of new antimalarial compounds: a multidisciplinary strategy aimed to search for potent chemical classes against new molecular targets and different stages of life of Plasmodium spp

Abstract

Malaria, a disease caused by protozoa of the genus Plasmodium spp., is one of the major public health problems in the world. The disease occurs in 87 countries, being endemic in the tropical and subtropical regions of Africa, Southeast Asia and Latin America. Half of the world's population (3.3 billion people) is exposed to Malaria transmission in high-risk areas. In 2018, 228 million cases and 405 thousand deaths were registered according to the World Health Organization (WHO). The emergence of drug resistance cases makes it extremely important to select new molecular targets in the parasite and the development of innovative chemotherapeutic agents against the disease. In this context, the search for drugs that act against different stages of the life cycle of the parasite and have an elucidated mechanism of action is of fundamental importance. This project aims to broaden the multidisciplinary approach inherent in the drug discovery process through the implementation of a new research line at UNIFESP - Baixada Santista, an emerging research center. In this sense, we intend to: (i) test the new classes of compounds against a panel of resistant strains; (ii) evaluate the speed of action of the new compounds in vitro; (iii) to elucidate the mechanism of action of the compounds using confocal microscopy and generation of P. falciparum strains resistant to new compounds to elucidate the target and the genes involved in the emergence of resistance; (iv) following the identification of potential mechanisms of action, we aim to develop new in silico models of ligand-protein complexes using homology modeling and molecular docking; (v) implement P. falciparum gametocyte culture in vitro to evaluate the activity of new classes of compounds; (vi) to confirm the activity of the most promising compounds against P. vivax in the artificial feeding model of Anopheles darlingi, (vii) determine the potential for inhibition of the most promising candidates against isolates of P. vivax and P. falciparum from Brazilian Amazon, using cryopreserved and fresh samples; (viii) evaluate the in vivo activity against P. berghei. The project will be developed in collaboration with different national and international research centers, among them: Federal University of São Paulo (UNIFESP), Center for Research and Innovation in Biodiversity and Drug Discovery - CIBFar-CEPID of the Institute of Physics of São Carlos-USP, Center of Tropical Medicine of rondônia (Porto Velho), Osvaldo Cruz Foundation - RO, Medicines for Malaria Venture, London School of Hygiene & Tropical Medicine (UK) and Department of Pharmaceutical Chemistry (University of California). (AU)