Histone deacetylase enzymes of cestode parasites, characterization as potential drug targets of neglected diseases

VACA, HUGO; AGUSTINA TOSCANINI; CELENTANO, ANA M.; MARIA LUJAN CUESTAS; CAMICIA, F.; ALEJANDRO NUSBLAT; ROSENZVIT, M.C.

Buenos Aires

Congreso; Drug Discovery for Neglected Diseases International Congress 2018 4th Scientific Meeting of ResNet NPND; 2018

Instituto de la Química y Metabolismo del Fármaco, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires

Echinococcosis is a disease caused by the cestode parasite Echinococcus granulosus. This disease represents a significant problem in human and animal health and is considered neglected and a priority matter for the WHO1. Currently, albenzadole is the only drug licensed available in Argentina for treatment. Therefore, it is very important to identify new alternative drugs against these parasites. Epigenetic mechanisms play an important role in the chromatin structure and, consequently, in regulation of gene expression and other cellular processes. Specifically, histone deacetylase enzymes (HDACs) have been validated as drug targets for the treatment of cancer and other diseases, including parasitic infections2,3. Our aim is to study the epigenetic mechanisms used by these helminths that may be suited for chemotherapy intervention. In this work we characterize cestode HDACs as possible drug targets. First we performed a homology search for HDAC on cestode genomes available on WormBaseParasite databank4. HDAC domains were identified in putative sequences and gene expression was confirmed by RNAseq data. The pan HDACs inhibitor ?Trichostatin A? (TSA) was used in Mesocestoides corti tetrathyridia (TTy), a cestode laboratory model. Viability, motility and morphology alterations of TSA-treated TTy were measured as well as the effect on parasite histone H4 acetylation and pan-acetylaled proteins by inmunoblot assay. HDAC genes of class I and II were found on cestodes genomes. All genes are expressed in different parasite stages of the Genus Echinococcus, being HDAC1 and HDAC8 differentially expressed in metacestode, the clinical relevant stage for human. TSA decreased by 40% the viability of TTy after 6 days treatment (P