? DESCRIPTION (provided by applicant): Intake of added sweeteners (high fructose corn syrup and sucrose) independently predicts the development of obesity, metabolic syndrome and diabetes. Despite recommendations by WHO and the AHA to reduce sugar intake to 5 to 10 percent of total energy intake, the mean intake of added sugars remains 15 percent of the diet, and 10 percent of the population ingest more than 25% of their diet as added sugars. While public health interventions may help reduce sugar intake, the addicting properties of sugar coupled with its ubiquitous presence in processed foods makes this a laudable challenge. Our group has focused on the biology by which sugar induces obesity and metabolic syndrome. We have identified fructokinase C as the key enzyme driving sugar-associated metabolic disorders. It is the ideal therapeutic target as fructokinase is specific for fructose metabolism and because people and mice lacking fructokinase are asymptomatic with normal lifespans. Moreover, mice lacking fructokinase are protected from developing obesity or insulin resistance in response to fructose, and while they appear to still like sugar, they ingest less sugar than normal mice suggesting that blocking fructokinase may help individuals reduce their sugar intake as opposed to the reverse. To date there is no drug available to block sugar-induced metabolic disorders or to block sugar craving, so developing a fructokinase inhibitor would be novel and significant. As such, Colorado Research Partners LLC (CRP) has initiated a drug development program. We have screened 1200 botanicals using a high-throughput enzymatic assay and identified >20 purified compounds that inhibit KHK-C with IC50s ranging from 0.25 to 15 ?M. We have also been able to show that some of these compounds are effective inhibitors in both cell culture and in vivo in the rat and mouse. We have further performed computer modeling (Schr?dinger software) of these compounds with the crystal structure of fructokinase C to evaluate binding energies and have identified 3 different scaffolds that can be synthetically modified using a smart drug design approach. Using structure-based drug design (SBDD) and pharmacophore modeling (virtual screening), we have identified over 750 derivatives with superior binding energies compared to the original prototypes. We have also assembled a team of chemists and biologists that will allow us to chemically prepare and test new chemical entities (NCEs) for inhibitory activity to fructokinase in cell-free systems, in cell culture, and in animal models. We now propose for this Phase I to generate NCEs based on these scaffolds that are active in the sub-micromolar (<100 nM) range. Our goal (milestone) is to develop at least 2 distinct compounds that are active in cell culture and in vivo (proof of mechanism) in a rodent model and that is specific for fructokinase compared to other sugar kinases (10:1 potency). Our goal at the end of phase I is to have several lead compounds that are ready for more detailed studies including pharmacokinetics, efficacy in long-term models of sugar-induced obesity and metabolic syndrome, and for intensive toxicology studies. We believe that the development of the first in a class of drug molecules to block sugar-based metabolism will represent a major breakthrough in the battle against obesity and diabetes.

R41DK104432

2015-09-15

2017-08-31