Piia Kokkonen

University of Eastern Finland, Kuopio Campus
Supervisor: Antti Poso, Maija Lahtela-Kakkonen
Funding: ISB
Date: 2012-01-01

Design of Sirtuin Regulators

Sirtuins are NAD+-dependent protein deacetylates which play key roles in cellular metabolism. They are now emerging as potential new drug targets because of their involvement in many diseases such as diabetes, neurodegenerative disorders and cancer. There are seven human sirtuins (SIRT1-7). The most studied sirtuin is SIRT1. There is growing interest for other sirtuins as they may provide the basis for novel therapeutic approaches against metabolic diseases. Especially, mitochondrial SIRT3 has been highlighted as one of the most interesting sirtuins since SIRT3 appears to suppress one of the contributing causes of aging itself, reactive oxygen species, and delay the onset of age-related pathologies in multiple tissues. On the other hand, SIRT3 has been associated with breast cancer, fatty liver, insulin resistance, radiation-induced liver steatosis, and age-associated hearing loss. SIRT3 is a fascinating novel target in balancing the mitochondrial dysfunctions.

In this study we aim to design novel selective regulators for SIRT3 and other sirtuins. We also aim to understand the interactions between sirtuins and their regulators in order to gain selectivity. We will use the new X-ray structure of SIRT3 (1) to screen in-house and commercial databases for regulators and to create a pharmacophore. The found ligands will be tested for activity with binding assays (2). The results of this study could provide new insights in mitochondrial enzyme regulation and novel potential sirtuin regulators.

The aims of this study are:
1. Designing selective sirtuin regulators.

So far several regulators of SIRT1 and SIRT2 have been tested with SIRT3 but selective regulators for SIRT3 have not been published. We aim to design novel compounds for SIRT3 by virtual screening of databases and synthetic modifications. A further aim regarding SIRT3 is to define pharmacophore in order to gain more specificity for SIRT3 regulators.

2. Identifying specificity in binding of SIRT3 ligands

There is compelling evidence that SIRT3 directly regulates the acetylation state and activity of target proteins. These include acetyl-CoA synthetase 2 (AceCS2), succinate dehydrogenase flavoprotein (SdhA) and cyclophilin D (CypD). As the crystal structures of SIRT3 and target proteins are available, protein-protein docking can be used for identifying binding as well as designing regulators.

3. Studying regulation of SIRT3 enzymes.

Understanding the regulation of mitochondrial enzymes and their associated pathways is essential to grasp how mitochondria function and adapt numerous metabolic processes and maintain cellular viability under the demands of diverse dietary input. Selective SIRT3 regulators could provide essential information on mitochondrial regulation mechanism, and give molecular insight into mitochondrial function and mitochondrial-based diseases.