THE POTENTIAL OF SIRTUIN ENZYMES AS DRUG TARGETS IN CESTODE PARASITES

CELENTANO, ANA M.; JUNG, MANFRED; VACA, HUGO R.; MACHIAROLLI, NATALIA; ROSENZVIT, MARA C.; TOSCANINI, AGUSTINA; ELISSONDO, MARÍA C.

CABA

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2021; 2021

SOCIEDADES DE BIOCIENCIAS

The anti-parasitic treatment of neglected tropical diseases (NTDs) caused by cestodes, such as echinococcosis and cysticercosis, relies on a small number of approved anthelmintics that are not well tolerated by some patients and often only partially effective. Thus, the identification of novel drug targets is critical. In this work, we identified Sirtuins (SIRTs), a family of NAD+-lysine deacetylases, in cestodes and evaluated their potential as drug targets. By bioinformatic analysis of genome data, we identified six SIRT-encoding genes -belonging to SIRTs classes I, III, and IV- in species from Echinococcus, Mesocestoides and Taenia genera. RNA-seq data analysis in Echinococcus spp. showed transcriptional expression of these genes throughout several developmental stages; being SIRT2 the most expressed SIRT gene in all analyzed stages. Furthermore, we experimentally determined the anthelmintic effect of SIRT inhibitors by a motility assay in the cestode model Mesocestoides vogae. The SIRT inhibitor Mz25 showed a strong and irreversible cestocidal activity at various concentrations. This activity was time and dose dependent and with a value of IC50 significantly lowers than that of the current anthelmintic albendazole. Ultrastructural features; studied by SEM showed that Mz25 induced extensive damage on the general morphology and highlighting damage at the tegument. Structural analysis by homology modeling showed a high conservation of the canonical SIRT structure for cestode SIRT2s. No mutations were found in the residues implicated in zinc coordination, or in those implicated in the binding to NAD+ cofactor or Mz25. However, some not conservative mutations were found in the selective pocket; representing a promising lead for developing selective cestode SIRT2s inhibitors. This report provides the basis for further studies to understand the roles of SIRTs in cestode biology and for developing selective inhibitors to treat NTDs caused by these parasites.