Banca de QUALIFICAÇÃO: RODRIGO CESAR FERNANDES BARBOSA

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : RODRIGO CESAR FERNANDES BARBOSA
DATE: 17/05/2024
TIME: 14:00
LOCAL: On line via Meet
TITLE:

Development of New HMG-CoA Reductase Inhibitors for the Treatment of Visceral Leishmaniasis

KEY WORDS:

Visceral leishmaniasis; HMG-CoA Reductase; Statins.

PAGES: 23
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Química dos Produtos Naturais
SUMMARY:

Studies involving rational synthesis of drugs are used in developing new medicines to combat neglected tropical diseases such as leishmaniasis. The enzyme HMG-CoA reductase (HMGR) acts at the beginning of the ergosterol and isoprenoid biosynthesis pathway present in Leishmania spp., and its inhibition by statins leads to the inhibition of the mevalonate pathway, including the biosynthesis of sterols and isoprenoid pyrophosphate. farnesyl and geranyl, responsible for the prenylation of several proteins, affecting different metabolic pathways of the parasite. In this sense, the development of drugs that inhibit HMGR and lead to a decrease in the production of ergosterol and isoprenoids may be a promising strategy for the treatment of visceral leishmaniasis. Therefore, this project aims to develop new leishmanicidal prototypes using HMGR from L. infantum as a pharmacological target for the treatment of Visceral Leishmaniasis (VL). Through molecular docking, the interactions of nine statins were compared with HMGR from L. infantum and H. sapiens, which present significant sequence divergences. The 5R, 6S, 6Z isomer of fluvastatin proved to be the most promising in terms of selectivity over the parasitic enzyme, being selected for carrying out structural modifications and phenotypic tests. The leishmanicidal activity and cytotoxicity of the synthesized derivatives will be evaluated in intracellular amastigotes to determine the IC50, and in murine peritoneal macrophages to determine the CC50, respectively. To evaluate the mechanism of action, sterols from parasites treated or not will be evaluated by GCMS. The leishmanicidal activity of the synthesized derivatives will be tested on L. infantum promastigotes that overexpress HMGR (LiHMGRhigh), in addition to evaluating the inhibition of protein prenylation. Compounds that show in vitro activity, low cytotoxicity and inhibit parasitic HMGR will be tested in a murine model of visceral leishmaniasis. At the end of the project, it is expected to obtain a set of experimental results on the inhibition of HMGR in a murine model, which will serve as a basis for suggesting the development of drugs that have statins as prototypes, and their use for the oral treatment of visceral leishmaniasis.

COMMITTEE MEMBERS:
Interno - 1220404 - CARLOS MAURICIO RABELLO DE SANT ANNA
Interna - 3145590 - DANIELA COSENTINO GOMES
Externo à Instituição - EDUARDO CAIO TORRES DOS SANTOS - FIOCRUZ