In this project, the investigators propose to develop novel treatment options for glutaric aciduria type 1 (GA1; MIM 231670). GA1 is an autosomal recessive inborn error of lysine, hydroxylysine and tryptophan degradation. Patients can present with brain atrophy and macrocephaly and may develop dystonia after acute encephalopathic crises triggered by intercurrent childhood infections that lead to striatal degeneration. The disorder is caused by a defect of glutaryl-CoA dehydrogenase (GCDH) due to mutations in GCDH, leading to the accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid. GA1 is considered a treatable disorder and therefore included in newborn screening programs in many countries. However, current treatment consists of dietary intervention, carnitine supplementation, and emergency treatment. This treatment paradigm requires intense efforts from both caregiver and patient. It must be strictly maintained because the risk of an acute crisis is always present. These limitations demonstrate the need for novel therapeutic options with improved efficacy and convenience. The investigators hypothesize that by using inhibitors upstream in the lysine degradation pathway, accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid in GA1 can be diverted into more tolerable metabolites. It has been shown that ?-aminoadipic and ?-ketoadipic aciduria is a biochemical phenotype without clinical significance. It is caused by mutations in DHTKD1 encoding the E1 subunit of ?- ketoadipic acid dehydrogenase, which is an enzyme upstream of GCDH. Therefore, the investigators propose that DHTKD1 is an excellent target for treatment of GA1. Thus the overall objective of this proposal is to identify novel small-molecule inhibitor leads for DHTKD1 suitable for future medicinal chemistry optimization.
In AIM 1, the investigators will identify enzyme inhibitor candidates through a small molecule high-throughput screen (HTS) and computational (virtual) screening using a molecular model of the DHTKD1 protein structure. The verified hits from the HTS will be used to improve the model then to explore, using computational and medicinal chemistry methods, a larger chemical space to find analogs for structure-activity relationships or new drug-like scaffolds. All active hits from the HTS and virtual screening will be further evaluated in AIM 2 in order to generate a prioritized list of commercial compounds with good medicinal chemistry properties.
In AIM 3 selected lead molecules will be tested in vitro in a cellular model of GA1 by monitoring established biomarkers for the inhibition of DHTKD1 and the disease. Combined these three aims will yield not only lead inhibitors of DHTKD1 that can be further developed for treatment of GA1, but also important additional data on the biochemistry and physiology of lysine degradation.

Public Health Relevance

Glutaric aciduria type 1 is an inborn error of lysine degradation. This genetic disorder has been included in newborn screening programs, but the current therapeutic intervention needs improvement. The investigators have identified a potential drug target and will develop small molecules that can serve as lead inhibitors in a translational drug discovery program.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Parisi, Melissa
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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