MULTIPLATFORM METABOLOMICS IN THE STUDY OF NEGLECTED DISEASES

• Grant number: 23/07993-7
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2025
• End date: February 29, 2028
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Analytical Chemistry
• Principal Investigator: Marina Franco Maggi Tavares
• Grantee: Marina Franco Maggi Tavares
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Alcindo Aparecido dos Santos ; Carolina Borsoi Moraes ; Eliana Nakano ; João Pedro Simon Farah ; Lucio Holanda Gondim de Freitas Junior

Abstract

The Center for Multiplatform Metabolomics Studies (CEMM) at IQ-USP, implemented during the COVID-19 pandemics (August 2020), inaugurated a novel research front, that intends to explore the potential of targeted and untargeted multiplatform metabolomics (by multiplatform it is meant the use of several hyphenated instrumental analytical techniques), to reveal the mechanism of action at molecular level of candidate drugs to the treatment of infectious and parasitic diseases. Among the diseases of interest at the moment there are included infectious diseases: chikungunya and yellow fever (arboviruses), both neglected in Brazil, and COVID-19, considered an emergent disease; in addition there are included several neglected parasitic diseases: leishmaniasis (visceral form is re-emergent) and Chagas disease, both caused by protozoa, and schistosomiasis, caused by helminths. There are hundreds of compounds being screened at the moment for an impressive number of diseases at ICB-USP, using high-throughput screening (HTS) and/or high-content screening (HCB) techniques; such compounds result from the efforts of CEMM collaborators, locally and abroad, working on the synthesis, extraction, purification, as well as theoretical calculations, and they are originated from computer simulations, natural products, synthetic chemicals libraries, and drug repositioning.The project here proposed is inserted in this wide line of research and aims at elucidating specifically the mechanism of action of organo-chalcogen compounds containing Se and Te for three parasitic neglected diseases prioritized in Brazil: leishmaniasis, Chagas disease and schistossomiasis. Synthetic compounds of Se and Te from a 60 compound library are selected a priori from in vitro experiments for each disease (including HTS and/or HCB), directly at the parasite or at infected and treated host cells. Cell extracts containing the hit compounds and the reference compounds (active principle of the drug in clinical use) will be prepared for further comparative metabolomics studies. The metabolic contents of cell extracts will be investigated by untargeted multiplatform metabolomics using three separation techniques hyphenated to mass spectrometry: gas chromatography (GC-MS/MS) and liquid chromatography in the modes reversed phase (RPLC-MS/MS) and hydrophilic interaction (HILIC-MS/MS), for wide metabolic coverage. Uni- and multi-variate techniques will indicate the discriminatory metabolites between the control and test groups (parasite treated versus non-treated, 2 groups; host cells, infected or not, treated or not, 4 groups, for the hit and reference compounds). The discriminating metabolites will then be identified for comparison of mass spectra and/or chromatographic characteristics at public access databases and further associated to metabolic routes to compose a biological hypothesis that will contribute to enhance our knowledge about the mechanism of action of the candidate drug. Theoretical studies will also be performed, where molecular descriptors of the compounds from the chemical library will be correlated with retention data (QSRR, quantitative structure-retention relationships), obtained by MEKC (micellar elektrokinetic chromatography) experiments, as well as with biological activity (QSPR, quantitative structure-property relationships). (AU)