Evaluation of novel alternative therapies with synthetic drugs using in vitro and experimental models of Leishmania (L.) infantum chagasi

• Grant number: 12/18756-1
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2013
• End date: December 31, 2014
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: André Gustavo Tempone Cardoso
• Grantee: André Gustavo Tempone Cardoso
• Host Institution: Instituto Adolfo Lutz (IAL). Coordenadoria de Controle de Doenças (CCD). São Paulo , SP, Brazil
• Associated researchers: Andrés Jimenez Galisteo Jr ; Noemi Nosomi Taniwaki ; Renato Arruda Mortara
• Associated research grant(s): 13/50318-7 - Natural product-based drug design: novel compounds against Leishmania (L.) infantum, AP.R

Abstract

In the search for new therapies, drug repositioning has been a successful innovation strategy and exploited by big pharmaceutical companies. Basically, it consists in finding a new use of drugs for approved drugs, which has been considered a highly favorable strategy in the current scenario of protozoosis neglected as visceral leishmaniasis (VL). Considering that Leishmaniasis is distributed in 98 countries, with 12 million infected, it has been considered one of the major parasitic diseases for WHO. Considering the increase of cases of VL in unaffected regions, the reduced therapeutic arsenal and the high toxicity of drugs, there is a need for selecting new antiparasitic agents. This proposal aims to study new therapies using in vitro and in vivo models of Leishmania (L.) infantum chagasi, using the following approaches: i) repositioning drugs- in vitro screening of approved drugs and available in the market for different therapeutic purposes such as antipsychotics, antagonists of histamine receptors, benzodiazepines, among others, ii) study of the mechanism of action- cellular alterations of Leishmania will be evaluated by spectrofluorimetric techniques, flow cytometry, confocal microscopy and transmission electron microscopy in order study apoptosis, alteration of the permeability of the plasma membrane, disturbance of mitochondrial membrane potential, generation of reactive oxygen species (ROS), etc., iii) drug delivery systems (liposomes) - evaluation of the effectiveness of drugs, free or included into liposomes, using experimental infected hamsters, and quantifying treatment by real-time PCR. The discovery of approved drugs in clinical use for other diseases, as well as the exploration of its mechanisms of action in the parasite, could contribute to the selection of more effective therapies, reducing costs and time for the search of new drugs for neglected diseases. (AU)

Scientific publications

(14)

(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)

REIMAO, JULIANA QUERO; MESQUITA, JULIANA TONINI; FERREIRA, DAIANE DIAS; TEMPONE, ANDRE GUSTAVO. Investigation of Calcium Channel Blockers as Antiprotozoal Agents and Their Interference in the Metabolism of Leishmania (L.) infantum. Evidence-based Complementary and Alternative Medicine, 2016. (12/18756-1, 08/11434-3, 11/21970-2)

VARELA, MARINA T.; DIAS, ROBERTO Z.; MARTINS, LIGIA F.; FERREIRA, DAIANE D.; TEMPONE, ANDRE G.; UENO, ANDERSON K.; LAGO, JOAO HENRIQUE G.; FERNANDES, JOAO PAULO S.. Gibbilimbol analogues as antiparasitic agents-Synthesis and biological activity against Trypanosoma cruzi and Leishmania (L.) infantum. Bioorganic & Medicinal Chemistry Letters, v. 26, n. 4, p. 1180-1183, FEB 15 2016. (13/20479-9, 12/18756-1, 15/11936-2, 14/16564-3)

DA COSTA-SILVA, THAIS ALVES; GRECCO, SIMONE S.; DE SOUSA, FERNANDA S.; LAGO, JOAO HENRIQUE G.; MARTINS, EUDER G. A.; TERRAZAS, CESAR A.; VARIKUTI, SANJAY; OWENS, KATHERINE L.; BEVERLEY, STEPHEN M.; SATOSKAR, ABHAY R.; et al. Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from Nectandra leucantha. Journal of Natural Products, v. 78, n. 4, p. 653-657, APR 2015. (13/50318-7, 12/18756-1, 13/07275-5)

PINTO, ERIKA G.; SANTOS, ISABELA O.; SCHMIDT, THOMAS J.; BORBOREMA, SAMANTA E. T.; FERREIRA, VITOR F.; ROCHA, DAVID R.; TEMPONE, ANDRE G.. Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships. PLoS One, v. 9, n. 8, AUG 29 2014. (11/23703-1, 12/18756-1)

SANTOS, LUCIANA DE A.; CAVALHEIRO, ALBERTO J.; TEMPONE, ANDRE G.; CORREA, DANIELA S.; ALEXANDRE, TATIANA R.; QUINTILIANO, NATALIA F.; RODRIGUES-OLIVEIRA, ANDRE F.; OLIVEIRA-SILVA, DIOGO; MARTINS, ROBERTO CARLOS C.; LAGO, JOAO HENRIQUE G.. Antitrypanosomal Acetylene Fatty Acid Derivatives from the Seeds of Porcelia macrocarpa (Annonaceae). Molecules, v. 20, n. 5, p. 8168-8180, MAY 2015. (11/51739-0, 12/18756-1)

PINTO, ERIKA G.; DA COSTA-SILVA, THAIS A.; TEMPONE, ANDRE GUSTAVO. Histamine H1-receptor antagonists against Leishmania (L.) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes. Acta Tropica, v. 137, p. 206-210, SEP 2014. (11/23703-1, 12/18756-1)

VARELA, MARINA T.; LIMA, MARTA L.; GALUPPO, MARIANA K.; TEMPONE, ANDRE G.; DE OLIVEIRA, ALBERTO; LAGO, JOAO HENRIQUE G.; FERNANDES, JOAO PAULO S.. New alkenyl derivative from Piper malacophyllum and analogues: Antiparasitic activity against Trypanosoma cruzi and Leishmania infantum. CHEMICAL BIOLOGY & DRUG DESIGN, v. 90, n. 5, p. 1007-1011, NOV 2017. (12/18756-1, 13/50228-8, 15/11936-2, 16/00195-4)

REIMAO, JULIANA QUERO; MESQUITA, JULIANA TONINI; FERREIRA, DAIANE DIAS; TEMPONE, ANDRE GUSTAVO. Investigation of Calcium Channel Blockers as Antiprotozoal Agents and Their Interference in the Metabolism of Leishmania (L.) infantum. Evidence-based Complementary and Alternative Medicine, v. 2016, p. 9-pg., 2016-01-01. (11/21970-2, 12/18756-1, 08/11434-3)

BAPTISTA CANUTO, GISELE ANDRE; DORR, FABIANE; GHILARDI LAGO, JOAO HENRIQUE; TEMPONE, ANDRE GUSTAVO; PINTO, ERNANI; PIMENTA, DANIEL CARVALHO; SIMON FARAH, JOAO PEDRO; MANSO ALVES, MARIA JULIA; MAGGI TAVARES, MARINA FRANCO. New insights into the mechanistic action of methyldehydrodieugenol B towards Leishmania (L.) infantum via a multiplatform based untargeted metabolomics approach. METABOLOMICS, v. 13, n. 5, MAY 2017. (15/50075-2, 12/04601-6, 14/25494-9, 12/07361-6, 12/18756-1)

WULSTEN, IMKE E.; COSTA-SILVA, THAIS A.; MESQUITA, JULIANA T.; LIMA, MARTA L.; GALUPPO, MARIANA K.; TANIWAKI, NOEMI N.; BORBOREMA, SAMANTA E. T.; DA COSTA, FERNANDO B.; SCHMIDT, THOMAS J.; TEMPONE, ANDRE G.. Investigation of the Anti-Leishmania (Leishmania) infantum Activity of Some Natural Sesquiterpene Lactones. Molecules, v. 22, n. 5, MAY 2017. (12/18756-1, 13/50228-8)

MARTINS, LIGIA F.; MESQUITA, JULIANA T.; PINTO, ERIKA G.; COSTA-SILVA, THAIS A.; BORBOREMA, SAMANTA E. T.; GALISTEO JUNIOR, ANDRES J.; NEVES, BRUNO J.; ANDRADE, CAROLINA H.; AL SHUHAIB, ZAINAB; BENNETT, ELLIOT L.; et al. Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes. Journal of Natural Products, v. 79, n. 9, p. 2202-2210, SEP 2016. (12/18756-1, 11/23703-1, 13/07275-5, 13/50228-8)

MESQUITA, JULIANA TONINI; PINTO, ERIKA GRACIELLE; TANIWAKI, NOEMI NOSOMI; GALISTEO, JR., ANDRES JIMENEZ; TEMPONE, ANDRE GUSTAVO. Lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide via induction of oxidative stress in Leishmania (L.) infantum. Acta Tropica, v. 128, n. 3, p. 666-673, DEC 2013. (12/18756-1)

MESQUITA, JULIANA TONINI; DA COSTA-SILVA, THAIS ALVES; TREIGER BORBOREMA, SAMANTA ETEL; TEMPONE, ANDRE GUSTAVO. Activity of imidazole compounds on Leishmania (L.) infantum chagasi: reactive oxygen species induced by econazole. Molecular and Cellular Biochemistry, v. 389, n. 1-2, p. 293-300, APR 2014. (12/18756-1)

MORAIS, THIAGO R.; DA COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; BORBOREMA, SAMANTA ETEL T.; SCOTTI, MARCUS T.; DE SOUSA, RAQUEL MARIA F.; ARAUJO, ANA CAROLINA C.; DE OLIVEIRA, ALBERTO; DE MORAIS, SERGIO ANTONIO L.; SARTORELLI, PATRICIA; et al. Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus terebinthifolius (Anacardiaceae): Structure/Activity Relationships. Molecules, v. 19, n. 5, p. 5761-5776, MAY 2014. (11/51739-0, 13/16320-4, 12/18756-1)