Título: Evaluation of HMG-CoA reductase and NPC1L1 as targets for drug repositioning of statins and ezetimibe as novel anthelmintics.
Disertante: Marina Monteiro Guedes
Institución: Laboratório de Genômica Estrutural e Funcional and Programa de Pós-Graduação em Biologia Celular e Molecular, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul. Porto Alegre, RS, Brazil.
Director/a: Henrique Bunselmeyer Ferreira
Resumen:
Cestodiases, like echinococcoses and cysticercoses, represent a global health problem. Currently available anthelmintics, as benzimidazoles and praziquantel, have limited effectiveness against visceral cestodiases, creating a demand for the identification of new and more effective drugs. In this scenario, drug repositioning is an appealing strategy. In this ongoing project, the potential of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and of Niemann-Pick C1 Like 1 (NPC1L1) protein as therapeutic targets is being investigated, assessing the repositioning of their available inhibitors as novel anthelmintics. HMG-CoA reductase, which can be inhibited by statins, is the main enzyme in the mevalonate pathway, essential for the synthesis of non-steroidal isoprenoids and the maintenance of normal cell functioning. NPC1L1, which can be inhibited by ezetimibe, is the main component of the mechanism of cholesterol absorption in metazoans, including cestodes. To evaluate the degree of conservation of HMG-CoA reductase and NPC1L1 among parasitic helminths and their respective hosts, the amino acid sequences of HMG-CoA reductase orthologs and the amino acid sequences of NPC1L1 orthologs were retrieved from public databases, compared and used for to build phylogenetic trees. Moreover, the 3D structures of HMG-CoA reductase and NPC1L1 were modeled for some cestode species, and their possible forms of interaction with the specific inhibitor were assessed by molecular docking. The possible effects of statins and ezetimibe on M. corti larvae (tetrathyridia) are now under assessment in vitro.
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