Evaluation of candidate drugs for the treatment of Leishmaniasis in Brazil

• Grant number: 15/09080-2
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2015
• End date: January 31, 2018
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Silvia Reni Bortolin Uliana
• Grantee: Silvia Reni Bortolin Uliana
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Adriano Cappellazzo Coelho ; Edgar Marcelino de Carvalho Filho ; Juliana Quero Reimão Dalla Zanna ; Paulo Roberto Lima Machado

Abstract

The various clinical forms of leishmaniasis are highly prevalent diseases in Brazil. In recent years, the classical, predominantly rural, geographical distribution of the disease has changed and we have witnessed a considerable increase in the number of urban cases. Only a few drugs are available for leishmaniasis treatment and these display several disadvantages such as high cost and toxicity, parenteral use and, in some instances, low efficacy due to selection of resistant parasites. The repositioning to leishmaniasis chemotherapy of two antineoplasic drugs, miltefosine and tamoxifen, has been proposed in the last few years. Miltefosine has already been approved for clinical use in some countries and tamoxifen has been shown to be effective in pre-clinical settings. This proposal is focused at contributing for the identification and/or validation of new alternatives for leishmaniasis chemotherapy. Specific aims are: (1) to evaluate the efficacy of the association of tamoxifen and meglumine antimoniate in a phase II pilot clinical test in localized cutaneous leishmaniasis patients; (2) investigate the leishmanicidal mechanisms of action of tamoxifen against Leishmania; (3) determine the antileishmanial activity of synthetic compounds structurally related to previously studied selective modulators of the estrogen receptor and (4) to contribute in the evaluation of the potential efficacy of miltefosine in Brazil - this is to be accomplished through determining the susceptibility of Brazilian Leishmania isolates to miltefosine and studying the molecular basis of differences in susceptibility. (AU)

Scientific publications

(18)

(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)

TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; BONANO, I, VIVIAN; ESPADA, CAROLINE R.; MIGUEL, DANILO C.; YOKOYAMA-YASUNAKA, JENICER K. U.; ULIANA, SILVIA R. B.. Topical tamoxifen in the therapy of cutaneous leishmaniasis. Parasitology, v. 145, n. 4, SI, p. 490-496, APR 2018. (15/05130-5, 11/18858-6, 15/09080-2, 11/20484-7, 11/21970-2)

CARIDHA, DIANA; VESELY, BRIAN; VAN BOCXLAER, KATRIEN; ARANA, BYRON; MOWBRAY, CHARLES E.; RAFATI, SIMA; ULIANA, SILVIA; REGUERA, ROSA; KREISHMAN-DEITRICK, MARA; SCIOTTI, RICHARD; et al. Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 11, n. SI, p. 106-117, DEC 2019. (15/09080-2)

ESPADA, CAROLINE R.; RIBEIRO-DIAS, FATIMA; DORTA, MIRIAM L.; DE ARAUJO PEREIRA, LEDICE INACIA; DE CARVALHO, EDGAR M.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; YOKOYAMA-YASUNAKA, JENICER K. U.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B.. Susceptibility to Miltefosine in Brazilian Clinical Isolates of Leishmania (Viannia) braziliensis. American Journal of Tropical Medicine and Hygiene, v. 96, n. 3, p. 656-659, 2017. (15/05130-5, 15/09080-2, 12/14629-5, 11/20484-7)

COELHO, ADRIANO C.; OLIVEIRA, JORDANA C.; ESPADA, CAROLINE R.; REIMAO, JULIANA Q.; TRINCONI, CRISTIANA T.; ULIANA, SILVIA R. B.. A Luciferase-Expressing Leishmania braziliensis Line That Leads to Sustained Skin Lesions in BALB/c Mice and Allows Monitoring of Miltefosine Treatment Outcome. PLoS Neglected Tropical Diseases, v. 10, n. 5, MAY 2016. (15/05130-5, 11/18858-6, 12/14629-5, 15/09080-2, 11/20484-7)

ALVES FERREIRA, RAFAEL AUGUSTO; REZENDE JUNIOR, CELSO DE OLIVEIRA; GRIGOL MARTINEZ, PABLO DAVID; KOOVITS, PAUL JOHN; SOARES, BRUNA MIRANDA; FERREIRA, LEONARDO L. G.; MICHELAN-DUARTE, SIMONE; CHELUCCI, RAFAEL CONSOLIN; ANDRICOPULO, ADRIANO D.; GALUPPO, MARIANA K.; et al. 2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling. PLoS Neglected Tropical Diseases, v. 15, n. 2, FEB 2021. (15/09080-2, 15/50655-9, 13/07600-3)

MACHADO, PAULO R. L.; RIBEIRO, CAMILA S.; FRANCA-COSTA, JAQUELINE; DOURADO, MAYRA E. F.; TRINCONI, CRISTIANA T.; YOKOYAMA-YASUNAKA, JENICER K. U.; MALTA-SANTOS, HAYNA; BORGES, VALERIA M.; CARVALHO, EDGAR M.; ULIANA, SILVIA R. B.. Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial. TROPICAL MEDICINE & INTERNATIONAL HEALTH, v. 23, n. 9, p. 7-pg., 2018-09-01. (15/09080-2)

ULIANA, SILVIA R. B.; TRINCONI, CRISTIANA T.; COELHO, ADRIANO C.. Chemotherapy of leishmaniasis: present challenges. Parasitology, v. 145, n. 4, SI, p. 464-480, APR 2018. (15/09080-2, 12/14629-5, 15/23832-7)

ESPADA, CAROLINE R.; MAGALHAES, RUBENS M.; CRUZ, MARIO C.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; CARVALHO, EDGAR M.; HORNILLOS, VALENTIN; ALVES, JOAO M.; CRUZ, ANGELA K.; COELHO, ADRIANO C.; et al. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 11, n. SI, p. 139-147, DEC 2019. (15/09080-2, 12/14629-5, 16/23405-4, 11/20484-7)

TRINCONI, CRISTIANA T.; MIGUEL, DANILO C.; SILBER, ARIEL M.; BROWN, CHRISTOPHER; MINA, JOHN G. M.; DENNY, PAUL W.; HEISE, NORTON; ULIANA, SILVIA R. B.. Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 8, n. 3, p. 475-487, DEC 2018. (15/09080-2, 11/18858-6)

TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; COELHO, ADRIANO C.; ULIANA, SILVIA R. B.. Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis. Journal of Antimicrobial Chemotherapy, v. 71, n. 5, p. 1314-1322, MAY 2016. (11/18858-6, 12/14629-5, 15/09080-2, 11/20484-7, 11/21970-2)

ESPADA, CAROLINE R.; ORTIZ, PAOLA A.; SHAW, JEFFREY J.; BARRAL, ALDINA M. P.; COSTA, JACKSON M. L.; ULIANA, SILVIA R. B.; COELHO, ADRIANO C.. Identification of Leishmania (Viannia) species and clinical isolates of Leishmania (Leishmania) amazonensis from Brazil using PCR-RFLP of the heat-shock protein 70 gene reveals some unexpected observations. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE, v. 91, n. 4, p. 312-318, AUG 2018. (15/09080-2, 12/14629-5, 16/23405-4, 11/20484-7)

ULIANA, SILVIA R. B.; TRINCONI, CRISTIANA T.; COELHO, ADRIANO C.. Chemotherapy of leishmaniasis: present challenges. Parasitology, v. 145, n. 4, p. 17-pg., 2018-04-01. (15/23832-7, 15/09080-2, 12/14629-5)

TRINCONI, CRISTIANA T.; REIMAO, JULIANA Q.; BONANO, VIVIAN, I; ESPADA, CAROLINE R.; MIGUEL, DANILO C.; YOKOYAMA-YASUNAKA, JENICER K. U.; ULIANA, SILVIA R. B.. Topical tamoxifen in the therapy of cutaneous leishmaniasis. Parasitology, v. 145, n. 4, p. 7-pg., 2018-04-01. (11/18858-6, 15/09080-2, 11/21970-2, 11/20484-7, 15/05130-5)

ESPADA, CAROLINE R.; MAGALHAES, RUBENS M.; CRUZ, MARIO C.; MACHADO, PAULO R.; SCHRIEFER, ALBERT; CARVALHO, EDGAR M.; HORNILLOS, VALENTIN; ALVES, JOAO M.; CRUZ, ANGELA K.; COELHO, ADRIANO C.; et al. Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 11, p. 9-pg., 2019-12-01. (12/14629-5, 15/09080-2, 11/20484-7, 16/23405-4)

CARIDHA, DIANA; VESELY, BRIAN; VAN BOCXLAER, KATRIEN; ARANA, BYRON; MOWBRAY, CHARLES E.; RAFATI, SIMA; ULIANA, SILVIA; REGUERA, ROSA; KREISHMAN-DEITRICK, MARA; SCIOTTI, RICHARD; et al. Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 11, p. 12-pg., 2019-12-01. (15/09080-2)

ESPADA, CAROLINE R.; FERREIRA, BIANCA A.; ORTIZ, PAOLA A.; ULIANA, SILVIA R. B.; COELHO, ADRIANO C.. Full nucleotide sequencing of ribosomal DNA internal transcribed spacer of Leishmania species causing cutaneous leishmaniasis in Brazil and its potential for species typing. Acta Tropica, v. 223, NOV 2021. (12/14629-5, 16/23405-4, 16/21171-6, 15/09080-2, 11/20484-7)

ESPADA, CAROLINE R.; ALBUQUERQUE-WENDT, ANDREIA; HORNILLOS, VALENTIN; GLUENZ, EVA; COELHO, ADRIANO C.; ULIANA, SILVIA R. B.. Ros3 (Lem3p/CDC50) Gene Dosage Is Implicated in Miltefosine Susceptibility in Leishmania (Viannia) braziliensis Clinical Isolates and in Leishmania (Leishmania) major. ACS INFECTIOUS DISEASES, v. 7, n. 4, p. 849-858, APR 9 2021. (15/09080-2, 18/25299-2, 16/23405-4, 16/21171-6)

DE OLIVEIRA REZENDE JR, CELSO; MARTINEZ, PABLO DAVID GRIGOL; FERREIRA, RAFAEL AUGUSTO ALVES; KOOVITS, PAUL JOHN; SOARES, BRUNA MIRANDA; FERREIRA, LEONARDO L. G.; MICHELAN-DUARTE, SIMONE; CHELUCCI, RAFAEL CONSOLIN; ANDRICOPULO, ADRIANO D.; MATHEEUSSEN, AN; et al. Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 246, p. 10-pg., 2023-01-15. (13/07600-3, 15/50655-9, 15/09080-2)