Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi In Vitro and In Vivo

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorPANDEY, Ramendra P.
dc.contributor.authorNASCIMENTO, Marilda Savoia
dc.contributor.authorFRANCO, Caio Haddad
dc.contributor.authorBORTOLUCI, Karina
dc.contributor.authorSILVA, Marcelo Nunes
dc.contributor.authorZINGALES, Bianca
dc.contributor.authorGIBALDI, Daniel
dc.contributor.authorBARRIOS, Leda Castano
dc.contributor.authorLANNES-VIEIRA, Joseli
dc.contributor.authorCARISTE, Leonardo Moro
dc.contributor.authorVASCONCELOS, Jose Ronnie
dc.contributor.authorMORAES, Carolina Borsoi
dc.contributor.authorFREITAS-JUNIOR, Lucio H.
dc.contributor.authorKALIL, Jorge
dc.contributor.authorALCANTARA, Laura
dc.contributor.authorCUNHA-NETO, Edecio
dc.date.accessioned2022-12-21T13:17:42Z
dc.date.available2022-12-21T13:17:42Z
dc.date.issued2022
dc.description.abstractDrug combinations and drug repurposing have emerged as promising strategies to develop novel treatments for infectious diseases, including Chagas disease. In this study, we aimed to investigate whether the repurposed drugs chloroquine (CQ) and colchicine (COL), known to inhibit Trypanosoma cruzi infection in host cells, could boost the anti-T. cruzi effect of the trypanocidal drug benznidazole (BZN), increasing its therapeutic efficacy while reducing the dose needed to eradicate the parasite. The combination of BZN and COL exhibited cytotoxicity to infected cells and low antiparasitic activity. Conversely, a combination of BZN and CQ significantly reduced T. cruzi infection in vitro, with no apparent cytotoxicity. This effect seemed to be consistent across different cell lines and against both the partially BZN-resistant Y and the highly BZN-resistant Colombiana strains. In vivo experiments in an acute murine model showed that the BZN+CQ combination was eight times more effective in reducing T. cruzi infection in the acute phase than BZN monotherapy. In summary, our results demonstrate that the concomitant administration of CQ and BZN potentiates the trypanocidal activity of BZN, leading to a reduction in the dose needed to achieve an effective response. In a translational context, it could represent a higher efficacy of treatment while also mitigating the adverse effects of high doses of BZN. Our study also reinforces the relevance of drug combination and repurposing approaches in the field of Chagas disease drug discovery.eng
dc.description.indexMEDLINEeng
dc.description.sponsorshipFundacao de Amparo a Pesquisa de Sao Paulo FAPESP [16/15209-0]
dc.description.sponsorshipBrazilian Council for Research-CNPq [304620/20165, 304891/2019-3]
dc.description.sponsorshipFAPESP [2014/50708-2]
dc.description.sponsorshipCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior-CAPES [88887.353390/2019-00]
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq [141635/2014-2]
dc.description.sponsorshipCNPq [BPP 306037/2019-0]
dc.description.sponsorshipFundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro/FAPERJ [E-26/202.572/2019]
dc.identifier.citationANTIMICROBIAL AGENTS AND CHEMOTHERAPY, v.66, n.11, 2022
dc.identifier.doi10.1128/aac.00284-22
dc.identifier.eissn1098-6596
dc.identifier.issn0066-4804
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/50378
dc.language.isoeng
dc.publisherAMER SOC MICROBIOLOGYeng
dc.relation.ispartofAntimicrobial Agents and Chemotherapy
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright AMER SOC MICROBIOLOGYeng
dc.subjectChagas disease drug discoveryeng
dc.subjectdrug combinationeng
dc.subjectdrug repurposingeng
dc.subjectchloroquineeng
dc.subjectbenznidazoleeng
dc.subject.otherrandomized-trialeng
dc.subject.othercell invasioneng
dc.subject.otherposaconazoleeng
dc.subject.othercombinationeng
dc.subject.otherphagosomeeng
dc.subject.otherregimenseng
dc.subject.otherstrainseng
dc.subject.otherburdeneng
dc.subject.othermiceeng
dc.subject.wosMicrobiologyeng
dc.subject.wosPharmacology & Pharmacyeng
dc.titleDrug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi In Vitro and In Vivoeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryÍndia
hcfmusp.affiliation.countryisoin
hcfmusp.author.externalPANDEY, Ramendra P.:Univ Sao Paulo, Sch Med, Heart Inst, Lab Immunol, Sao Paulo, Brazil; Univ Sao Paulo, Sch Med, Sao Paulo, Brazil; SRM Univ, Ctr Drug Design Discovery & Dev C4D, Delhi NCR, Rajiv Gandhi Educ City, Sorepat, Haryana, India
hcfmusp.author.externalFRANCO, Caio Haddad:Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, Brazil
hcfmusp.author.externalBORTOLUCI, Karina:Univ Fed Sao Paulo, Dept Pharmacol, Sao Paulo, Brazil
hcfmusp.author.externalSILVA, Marcelo Nunes:Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo, Brazil
hcfmusp.author.externalZINGALES, Bianca:Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo, Brazil
hcfmusp.author.externalGIBALDI, Daniel:Inst Oswaldo Cruz Fiocruz, Rio De Janeiro, Brazil
hcfmusp.author.externalBARRIOS, Leda Castano:Inst Oswaldo Cruz Fiocruz, Rio De Janeiro, Brazil
hcfmusp.author.externalLANNES-VIEIRA, Joseli:Inst Oswaldo Cruz Fiocruz, Rio De Janeiro, Brazil
hcfmusp.author.externalCARISTE, Leonardo Moro:Univ Fed Sao Paulo, Dept Biosci, Recombinant Vaccines Lab, Sao Paulo, Brazil
hcfmusp.author.externalVASCONCELOS, Jose Ronnie:Univ Fed Sao Paulo, Dept Biosci, Recombinant Vaccines Lab, Sao Paulo, Brazil; Fed Univ Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, Sao Paulo, Brazil
hcfmusp.author.externalMORAES, Carolina Borsoi:Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, Brazil
hcfmusp.author.externalFREITAS-JUNIOR, Lucio H.:Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, Brazil
hcfmusp.citation.scopus5
hcfmusp.contributor.author-fmusphcMARILDA SAVOIA NASCIMENTO
hcfmusp.contributor.author-fmusphcJORGE ELIAS KALIL FILHO
hcfmusp.contributor.author-fmusphcLAURA DE ALCANTARA
hcfmusp.contributor.author-fmusphcEDECIO CUNHA NETO
hcfmusp.description.issue11
hcfmusp.description.volume66
hcfmusp.origemWOS
hcfmusp.origem.pubmed36314800
hcfmusp.origem.scopus2-s2.0-85141934143
hcfmusp.origem.wosWOS:000876920300001
hcfmusp.publisher.cityWASHINGTONeng
hcfmusp.publisher.countryUSAeng
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