Hydroxyproline Dehydrogenase Inhibitors for the Treatment of Primary Hyperoxaluria

PROJECT SUMMARY: The breakdown of hydroxyproline, a component of collagen within our bodies and in the meat that we consume, is a significant contributor to glyoxylate and oxalate levels. We have shown in normal individuals and patients with primary hyperoxaluria (PH) that hydroxyproline is converted to oxalate (18% for PH1, 47% for PH3, and 33% for PH3). These values are the largest known contribution to oxalate formation for any metabolite studied to date. We hypothesize that blocking the hydroxyproline pathway with a drug will significantly lower the glyoxylate and oxalate burden of PH2 and PH3 patients, for which there are no available therapies. The target of this study is the first enzyme in the hydroxyproline degradation pathway, hydroxyproline dehydrogenase (HYPDH). A drug that blocks HYPDH activity would prevent the formation of downstream metabolites that contribute to oxalate levels. This strategy is supported by the observation that individuals that are deficient in HYPDH are normal and safely excrete the excess hydroxyproline into their urine. Our team has made the HYPDH knockout mouse (Prodh2 gene) and shown that the mice are healthy and not affected by HYPDH deficiency. Moreover, we have shown that the HYPDH knockout in the PH2 mouse model protects the mice from oxalate production from hydroxyproline. Thus, inhibition of HYPDH shows promise for the prevention and treatment of PH. Our team has already performed high throughput screening assays and identified potent inhibitors of HYPDH. These inhibitors require further optimization to improve potency, selectivity, and drug-like properties. The proposed research program will combine our biochemical, cellular, structural biology, computational, and medicinal chemistry expertise to optimize the compounds. The following specific aims illustrate the iterative compound progression plan that will be employed: (Aim 1) to design and synthesize compounds that will explore the structure-activity-relationship (SAR) properties of HYPDH inhibitor scaffolds; (Aim 2) to determine the biochemical and cellular properties of HYPDH inhibitors; (Aim 3) to apply computational and structural biology approaches to determine the binding mode of HYPDH inhibitors to inform compound design and synthesis; and (Aim 4) to determine the efficacy of HYPDH inhibitors in a variety of PH mouse models.