Human sirtuin 2 inhibitors, their mechanisms and binding modes.

The silent information regulator (sirtuin) is a family of enzymes involved in epigenetic processes with lysine deacetylase activity, having as substrates histones and other proteins. They participate in a wide range of cellular and pathologic processes, such as gene expression, cell division and motility, oxidative-induced stress management, metabolic control and carcinogenesis, among others, thus presenting as interesting therapeutic targets. In this article, the authors describe the inhibitory mechanisms and binding modes of the human sirtuin 2 (hSIRT2) inhibitors, which had their complexes with the enzyme structurally characterized. The results help pave the way for the rational designing of new hSIRT2 inhibitors and the development of novel therapeutic agents targeting this epigenetic enzyme.

Parasitic sirtuin 2 as an opportunity in drug discovery.

Infections caused by protozoans remain a public health issue, especially in tropical countries. Serious adverse events, lack of efficacy at the different stages of the infection and routes of administration that have a negative impact on treatment adherence are some of the problems with currently available therapy against these diseases. Here we describe an epigenetic target, sirtuin 2 and its related proteins, that is promising given the results in phenotypic assays and in vivo models against Sir2 of Plasmodium falciparum, Leishmania donovani, Leishmania infantum, Schistosoma mansoni, Trypanosoma brucei and Trypanosoma cruzi parasites. The results we present highlight how this target can be extensively explored and how its inhibitors might be employed in the clinic.