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

• Grant number: 19/19708-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2021
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Anna Caroline Campos Aguiar
• Grantee: Anna Caroline Campos Aguiar
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Dhelio Batista Pereira ; Ernest Diez Benavente ; Glaucius Oliva ; Marcos Leoni Gazarini Dutra ; Rafael Victorio Carvalho Guido ; Susana Campino ; Wilian Augusto Cortopassi Coelho
• Associated scholarship(s): 25/11777-3 - Determination of the Phenotypic Profile of a Triazolopyrimidine Derivative., BP.IC; 24/03642-8 - Evaluation of a hybrid of piperaquine analogs and triazolopyrimidine as a candidate for a transmission-blocking antimalarial, mechanism of action studies, and inhibitory activity against circulating strains in Porto Velho-RO., BP.TT; 24/00143-0 - Characterization of adapted P. falciparum isolates aiming to evaluate new compounds against sexual and asexual stages of the parasite's life cycle., BP.IC; + associated scholarships 23/09653-9 - Phenotypical Analysis of a compound derived from the marine bacteria Rapidithrix thailandica as an antimalaric candidate, BP.MS; 22/05873-1 - Activity evaluation of new 4-quinolone compounds against sexual forms of Plasmodium spp., BP.MS; 21/12162-1 - Determination of the speed of action of new hits against asexual forms of P. falciparum in vitro, BP.IC - associated scholarships

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)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MARTIGNAGO, CINTIA CRISTINA SANTI; SOARES-SILVA, BEATRIZ; PARISI, JULIA RISSO; SILVA, LAIS CAROLINE SOUZA E; GRANITO, RENATA NEVES; RIBEIRO, ALESSANDRA MUSSI; RENNO, ANA CLAUDIA MUNIZ; DE SOUSA, LORENA RAMOS FREITAS; AGUIAR, ANNA CAROLINE CAMPOS. Terpenes extracted from marine sponges with antioxidant activity: a systematic review. NATURAL PRODUCTS AND BIOPROSPECTING, v. 13, n. 1, p. 12-pg., 2023-12-01. (19/10228-5, 19/19708-0)

DE VRIES, LAURA E.; JANSEN, PATRICK A. M.; BARCELO, CATALINA; MUNRO, JUSTIN; VERHOEF, JULIE M. J.; PASAJE, CHARISSE FLERIDA A.; RUBIANO, KELLY; STRIEPEN, JOSEFINE; ABLA, NADA; BERNING, LUUK; et al. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. NATURE COMMUNICATIONS, v. 13, n. 1, p. 16-pg., 2022-04-20. (13/07600-3, 19/19708-0, 20/12904-5)

BARBOSA, CAMILA S.; AHMAD, ANEES; MALUF, SARAH EL CHAMY; MOURA, IGOR M. R.; SOUZA, GUILHERME E.; GUERRA, GIOVANNA A. H.; BARROS, ROBERTO R. MORAES; GAZARINI, MARCOS L.; AGUIAR, ANNA C. C.; BURTOLOSO, ANTONIO C. B.; et al. Synthesis, Structure-Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium falciparum Inhibitors. PHARMACEUTICALS, v. 15, n. 7, p. 21-pg., 2022-07-01. (13/07600-3, 21/03977-1, 20/14429-2, 19/17721-9, 19/19708-0, 20/12904-5, 18/06219-8, 15/20084-0, 18/07287-7, 13/18009-4, 21/14319-5)

CORTOPASSI, WILIAN A.; GUNDERSON, EMMA; ANNUNCIATO, YASMIN; SILVA, ANTONY. E. S.; FERREIRA, AMALIA DOS SANTOS; TELES, CAROLINA BIONI GARCIA; PIMENTEL, ANDRE S.; RAMAMOORTHI, ROOPA; GAZARINI, MARCOS L.; MENEGHETTI, MARIO R.; et al. Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 20, p. 8-pg., 2022-11-11. (13/07600-3, 19/19708-0, 20/12904-5)

MARTIGNAGO, CINTIA CRISTINA SANTI; BARBOSA, CAMILA DE SOUZA; MOTTA, HOMERO GARCIA; SOARES-SILVA, BEATRIZ; PERES, ERICA PALOMA MASO LOPES; SILVA, LAIS CAROLINE; BONIFACIO, MIRIAN; SOUSA, KAROLYNE DOS SANTOS JORGE; ALQUALO, AMANDA SARDELI; PARISI, JULIA; et al. Exploring Antibacterial Properties of Marine Sponge-Derived Natural Compounds: A Systematic Review. MARINE DRUGS, v. 23, n. 1, p. 17-pg., 2025-01-01. (23/13928-3, 19/19708-0, 21/02974-9)

XIE, STANLEY C.; TAI, CHIA-WEI; MORTON, CRAIG J.; MA, LITING; HUANG, SHIH-CHUNG; WITTLIN, SERGIO; DU, YAWEI; HU, YONGBO; DOGOVSKI, CON; SALIMIMARAND, MINA; et al. A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo. PLOS PATHOGENS, v. 20, n. 12, p. 28-pg., 2024-12-01. (19/19708-0, 13/07600-3)

CAMPOS AGUIAR, ANNA CAROLINE; PARISI, JULIA RISSO; GRANITO, RENATA NEVES; FREITAS DE SOUSA, LORENA RAMOS; MUNIZ RENNO, ANA CLAUDIA; GAZARINI, MARCOS LEONI. Metabolites from Marine Sponges and Their Potential to Treat Malarial Protozoan Parasites Infection: A Systematic Review. MARINE DRUGS, v. 19, n. 3, MAR 2021. (19/19708-0)

DA SILVA NETO, GERALDO JOSE; SILVA, LEANDRO ROCHA; DE OMENA, RAFAEL JORGE MELO; AGUIAR, ANNA CAROLINE CAMPOS; ANNUNCIATO, YASMIN; ROSSETTO, BARBARA SANTOS; GAZARINI, MARCOS LEONI; HEIMFARTH, LUANA; QUINTANS-JUNIOR, LUCINDO JOSE; DA SILVA-JUNIOR, EDEILDO FERREIRA; et al. Dual quinoline-hybrid compounds with antimalarial activity against Plasmodium falciparum parasites. NEW JOURNAL OF CHEMISTRY, v. 46, n. 14, p. 17-pg., 2022-03-02. (19/19708-0)

CALIT, JULIANA; PRAJAPATI, SURENDRA K.; BENAVENTE, ERNEST D.; ARAUJO, JESSICA E.; DENG, BINGBING; MIURA, KAZUTOYO; ANNUNCIATO, YASMIN; MOURA, IGOR M. R.; USUI, MIHO; MEDEIROS, JANSEN F.; et al. Pyrimidine Azepine Targets the Plasmodium bc₁ Complex and Displays Multistage Antimalarial Activity. JACS AU, v. 4, n. 10, p. 11-pg., 2024-10-07. (18/24878-9, 21/06769-0, 19/19708-0, 23/02543-3)