Characterization of Histone deacetylase 8 isotype from cestodes as new potential drug targets of neglected diseases

AGUSTINA TOSCANINI; MARIA LUJAN CUESTAS; HUGO VACA; FEDERICO CAMICIA; MARA C. ROSENZVIT; ANA MARÍA CELENTANO; ALEJANDRO NUSBLAT

Mar del Plata

Congreso; Reunión Conjunta SAIC SAI SAFIS 2018; 2018

Sociedad Argentina de investigacion clinica (SAIC)

Echinococcosis and cysticercosis, tropical diseases caused by cestode parasites, represent a significant problem in human and animal health and are considered neglected and a priority matter for the WHO. Histone deacetylases (HDACs) have been validated as drug targets for the treatment of several diseases, including parasitic infections. HDACs remove acetyl groups from histones and other cellular effectors, thus directly influencing the chromatin structure and thereby regulating gene transcription and other cellular processes. Previously, we have shown the presence of HDAC genes of class I and II on cestode genomes and showed that they have an essential role in parasite development and survival. Specifically, HDAC8 was one of the more promising drug targets since it is expressed in different parasite stages of the genus Echinococcus and is up-regulated in the metacestode, the clinical relevant stage. Furthermore, HDAC8s showed only 40% amino acid identities with human HDAC8. In this work, we characterized HDAC8 from cestodes for the treatment of diseases they cause. We have cloned, sequenced and performed homology modelling and protein expression of HDAC8 from Echinococcus canadensis and Mesocestoides corti, a parasite used as a laboratory model of cestodes. Cestode HADC8s showed HDAC domain conservation with specific insertions compared to their human ortholog. Homology models adopted canonical α/β HDAC fold, the structures suggested that the catalytic pocket are conserved, only an amino acid is substituted and distinguished of human HDAC8, human M274 by histidine. Also, important res- idues implicated in binding to pan HDAC inhibitor ?Trichostatin A? (TSA) are conserved. Escherichia coli (BL21) was used as expression system to produce recombinant HDAC8 from both cestodes; the obtained proteins were of the expected molecular weight. Future studies will include HDAC8 activity inhibition assays with specific inhibitors. This work is the first step to study HDAC8 from cestodes as a possible new drug target.