A novel treatment option for disorders of propionate metabolism

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Project Summary / Abstract In this project, the investigators propose to develop a novel treatment option for disorders of propionate metabolism such as propionic acidemia (PA). PA patients may present with acute metabolic decompensation with hyperammonemia, and can develop a multisystem disorder or cardiomyopathy. The disorder is caused by propionyl-CoA carboxylase (PCC) deficiency due to biallelic mutations in PCCA or PCCB. PCC deficiency leads to the accumulation of propionyl-CoA and several organic acids, which are thought to be toxic. PA patients benefit from early intervention and the disorder has been included in newborn screening programs in many countries. Current treatments include acute and chronic interventions all aiming to reduce propiogenic precursors, but the outcome of PA is still unfavorable as many patients have long-term complications that can affect multiple organ systems. In addition, dietary management may lead to nutritional deficiencies in essential branched-chain amino acids (BCAAs). This illustrates the need for new therapeutic options that can further improve outcome in PA. The investigators hypothesize that by using inhibitors upstream in the propiogenic isoleucine and valine degradation pathways, accumulation of toxic propionyl-CoA and its derivatives can be diverted into more tolerable metabolites. Short/branched-chain acyl-CoA dehydrogenase (SBCAD) and isobutyryl-CoA dehydrogenase (ACAD8) are involved in the degradation of the BCAAs isoleucine and valine, respectively. Deficiencies SBCAD and ACAD8 are thought to be biochemical phenotypes without clinical significance. Published and preliminary data show that inhibition of SBCAD and ACAD8 limits metabolite accumulation in cell line models for PA. This suggests that SBCAD and ACAD8 are suitable and potentially safe targets for treatment of PA. Thus, the overall objective of this proposal is to identify and validate novel small-molecule SBCAD and ACAD8 inhibitors suitable for future medicinal chemistry optimization to candidate molecules. In AIM 1, the investigators will optimize enzyme assays for the screening of SBCAD and ACAD8 inhibitor candidates using recombinant proteins. Enzyme inhibitor candidates will be identified in AIM 2 through a computational (virtual) screening using reported crystal structures for human SBCAD and ACAD8. All hits from the virtual screening will be further evaluated in AIM 3 in order to generate a prioritized list of commercial compounds with good medicinal chemistry properties. In AIM 4 selected validated hit molecules will be tested in vitro in cell-based models of PA by monitoring established biomarkers for the inhibition of SBCAD and ACAD8, and the disease. Combined, these four aims will yield not only validated hit inhibitors of SBCAD and ACAD8 that can be further optimized for treatment of PA, but also important insights into the biochemistry and physiology of propionyl-CoA production.