Structure Based Design of SREBP Inhibitors

Synthesis and degradation of lipids, such as cholesterol and fat, requires careful synchronization. Disturbances of the lipid balance lead to serious human diseases including obesity, diabetes and even cancers. My work focuses on the Sterol Regulatory Element Binding Protein (SREBP) family of transcription factors. SREBPs are proteins that sit on molecular switches (sterol regulatory elements) that determine the rate of cholesterol and fat synthesis. As part of a global collaboration between Austria and the USA, we are engineering tools, known as inhibitors, to flip these switches to the Off position. This way, we intend to drastically reduce the rate of lipid synthesis. In this scenario, the human body would rely heavily on the uptake of cholesterol and lipids through diet and the mobilization of specialized fat depots from designated fatty tissue. Cancer cells rely on elevated lipid synthesis to fuel their rapid growth and protein pathways that are required to supply this elevated demand are known to be upregulated in many cancer cells. SREBPs sit on molecular switches of precisely these cancer pathways and their inhibition will constrict the rapid expansion of these transformed cells. SREBPs do not act by themselves. They need other proteins, designated co-activators, to help them turn their switches to the ON position. We identified three inhibitors, which disrupt the communication between SREBPs and their co-activators. Now we are working to improve their specificity and efficacy. Honing the SREBP inhibitors will assure that they reach their intended targets and minimize unintended side effects. Our main tool to advance our fat-busting research is nuclear magnetic resonance spectroscopy, a technique with the unique ability to visualize atomic structures in the sub- nanometer range. It allows us to measure distances between individual atoms within a molecule, or even between atoms of two different molecules. We use elaborate computer calculations and simulations to construct models from these experimentally derived measurements. These models allow us to visualize how SREBPs interact with their co- activators and how inhibitors disrupt these interactions. Guided by these models, we aim to synthesize optimal chemical and biological SREBP inhibitors. In addition to conventional small molecule inhibitors, we are also working on the development of biologic peptide inhibitors. We will modify appropriate peptides with novel methodologies to increase their stability and efficacy. Finally, we will combine the conventional and novel approaches and decorate chemically stabilized peptides with small molecule SREBP inhibitors. We hope to develop optimal SREBP inhibitors with this combined strategy, which would lead to the amelioration of human health by targeting obesity, diabetes and cancer.

Using a combination of structural biology, computational modeling, biophysical and computational high throughput screens, and biological assays, we developed a range of small molecule and peptidomimetics inhibitors of the bodies fatty and cholesterol synthesis pathway. We subsequently used these molecules to demonstrate that the blockade of fatty and cholesterol synthesis is a viable therapeutic venue to inhibit cancer growth and replication of enveloped viruses.