| Grant number: | 15/17623-6 |
| Support type: | Scholarships in Brazil - Master |
| Effective date (Start): | May 01, 2016 |
| Effective date (End): | February 28, 2018 |
| Field of knowledge: | Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology |
| Principal Investigator: | Luiz Felipe Domingues Passero |
| Grantee: | Eduardo Seiji Yamamoto |
| Home Institution: | Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
Abstract Leishmaniasis is an endemic disease present in 98 countries and is considered a neglected disease by the World Health Organization. Caused by parasite protozoans from Leishmania genus and transmitted by vectors, the disease may present clinical forms which vary from simple lesions that self-heal to the visceral form, which affects internal organs and leads to death if left non-treated. The treatment is still based on pentavalent antimonials and amphotericin, both causing many secondary effects; in addition, reports about resistance are constantly published. These facts demonstrate that alternative drugs must be developed for the chemotherapy of leishmaniasis. Thus, drug repurposing shows an important strategy for the developing of new therapeutic alternatives for leishmaniasis, because drugs already developed for human use may be reutilized, decreasing developing time and cost employed for the research of new ones. Leishmania sp. possess as a main lipid the ergosterol, whose metabolic pathway is complex and involves a series of enzymes, which if correctly blocked, may suppress the ergosterol production, and parasite viability. Considering these aspects, this project aims to repurposing drugs with ergosterol enzyme inhibition on leishmaniasis. For that the antihyperlipidemics rosuvastatin and prasvatatin, the antifungal drugs voriconazole, tiaconazole, fenticonazole, naftifin, nystatin and the antidepressant mianserin will be obtained commercially and their potential against promastigote forms from L. (L.) amazonensis, L. (L.) chagasi and L. (V.) braziliensis will be evaluated. The cytotoxic potential will be evaluated on J774 macrophages. In a next step, the same macrophage lineage will be infected with the species listed above, the drugs will be added and the potential against amastigote forms will be demonstrated using the infection index. The nitric oxide and hydrogen peroxide will be evaluated on the supernatant and/or intracellular environment of these cells. Ultrastructural alterations on promastigotes and intracellular amastigotes submitted to treatment will be evaluated through transmission electronic microscopy. Depending on the observed alteration, a specific methodology will be employed to evaluate a possible action mechanism from the drug on Leishmania sp. Considering that these drugs are capable of inhibiting different component from the ergosterol formation metabolic pathway, this suggests they are capable of inhibiting the parasite inside macrophages, which in fact, could lead to new strategies of treatment and revolutionize the current chemotherapy. | |