DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for dihydropyrimidinuria — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDihydropyrimidinuria maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for dihydropyrimidinuria is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
dihydropyrimidinase (DPYS) — DPYS is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2VR2 · 2.8 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A population study of 21,200 healthy Japanese infants found two cases of dihydropyrimidinuria without clinical symptoms, giving an estimated prevalence of roughly 1 in 10,000 births in Japan. In one family, a sister of the original adult case was newly identified as a second case because she excreted large amounts of dihydrouracil and dihydrothymine. The parents and the child of the propositus showed slight increases of those metabolites. A uracil loading test on the parents produced urinary dihydrouracil concentrations several times higher than in normal controls, consistent with heterozygote status. The pattern across the propositus, his sister, his child, and his parents indicates autosomal recessive inheritance. Homozygotes may have a high risk of 5-fluorouracil toxicity, while the risk is relatively low in heterozygotes.
A 32-month-old Chinese boy in Hong Kong presented with language development delay. Biochemical analysis showed markedly increased urinary excretion of dihydrouracil and dihydrothymine. DNA testing confirmed he was compound heterozygous for two missense mutations in the dihydropyrimidinase gene: one known (p.R302Q) and one novel (p.N16K). This was the first reported case of dihydropyrimidinase deficiency in a Chinese subject. The clinical presentation of dihydropyrimidinase deficiency is variable and has also been reported in asymptomatic subjects.
Urinary dihydrothymine and thymine were measured in 276 Japanese adults to establish reference ranges. Both metabolites were significantly higher in females. The reference ranges (mean plus or minus SD with logarithmic values) for males were 1.56 to 5.70 micromol per gram of creatinine for dihydrothymine and 0.40 to 1.47 micromol per gram of creatinine for thymine. For females the ranges were 1.89 to 8.33 micromol per gram of creatinine for dihydrothymine and 0.58 to 2.30 micromol per gram of creatinine for thymine. In one dihydropyrimidinuria case, both dihydrothymine and dihydrouracil were excreted in large amounts, outside the normal range. In a dihydropyrimidine dehydrogenase deficiency case, thymine concentrations in all urine samples were out of the reference range, but uracil levels in most samples were within normal range.
What is still missing is any systematic trial of a treatment for dihydropyrimidinuria itself, as opposed to screening for fluorouracil toxicity risk. No therapy has been tested in a controlled study. The natural history of the condition, especially in asymptomatic individuals identified by newborn screening, remains poorly characterised. Patient stratification by genotype and clinical outcome is absent, and funding for such work has not been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Medical Genetics · 1998 · 64 citations
Population and family studies of dihydropyrimidinuria: Prevalence, inheritance mode, and risk of fluorouracil toxicity
AbstractTo evaluate the prevalence of dihydropyrimidinuria (DHPuria), we analyzed urine samples from 21,200 healthy Japanese infants, and found two cases of DHPuria without clinical symptoms. Based on this result, we estimated the prevalence to be approximately 1/10,000 births in Japan. In addition, we analyzed pyrimidine catabolism on a previously reported family with an adult DHPuria case. We newly identified the sister of the propositus as the second case of DHPuria in this family, because she excreted large amounts of dihydrouracil and dihydrothymine. The parents and the child of the propositus showed slight increases of dihydrouracil and dihydrothymine. This is the first family with 2 cases of DHPuria, indicating that DHPuria is an inherited condition. To determine the inheritance of DHPuria in this family and to examine the risk of 5-fluorouracil (5-FU) toxicity, a uracil loading test was performed on the parents. Urinary dihydrouracil concentrations in the parents after the loading were several times higher than those in normal control persons, the finding being consistent with DHPuria heterozygotes. This, along with data on the propositus, his sister, and his child, indicates that DHPuria is an autosomal recessive condition. In addition, DHPuria homozygotes may have a high risk of 5-FU toxicity, while the risk is relatively low in heterozygotes.
Hong Kong Medical Journal · 2013 · 14 citations · open access
Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria
AbstractDihydropyrimidinase deficiency is an autosomal recessive inborn error of metabolism characterised by the presence of dihydropyrimidinuria. Its clinical presentation is variable and has also been reported in asymptomatic subjects. We report the first case of dihydropyrimidinase deficiency in Hong Kong, which is also the first reported in a Chinese subject. The patient was a 32-month-old boy who presented with language development delay. Biochemical analysis confirmed markedly increased urinary excretion of dihydrouracil and dihydrothymine, whilst DNA testing confirmed that the patient was compound heterozygous for two missense mutations, one known (p.R302Q) and the other was novel (p.N16K).
International Journal of Molecular Medicine · 1998 · 12 citations
Possible prediction of adverse reactions to fluorouracil by the measurement of urinary dihydrothymine and thymine.
AbstractDihydropyrimidine dehydrogenase (DPD) deficiency with a defect of the pyrimidine catabolic pathway has recently become the focus of considerable attention, due to the severe 5-fluorouracil (5-FU) toxicities occurring in DPD deficiency patients. Studies also suggest that 5-FU toxicities could occur in another pyrimidine metabolic disorder, dihydropyrimidinuria (DHPuria). This study shows that urinary dihydrothymine (DHT) and thymine (THY) are useful indexes for detection of DPD deficiency and DHPuria. We measured urinary DHT and THY in 276 Japanese adults to establish reference ranges. When males and females were compared, both DHT and THY levels were found to be significantly higher in females. The reference ranges (mean +/- SD with logarithmic values) for males were found to be 1.56-5.70 micromol/g of creatinine for DHT and 0.40-1.47 micromol/g of creatinine for THY. The reference ranges for females were found to be 1.89-8.33 micromol/g of creatinine for DHT and 0.58-2.30 micromol/g of creatinine for THY. In addition to this study we analyzed a DPD deficiency case and a DHPuria case. In the DPD deficiency case, the THY concentrations of all urine samples were out of the reference range. However, uracil levels in most of the samples were within the normal range. The DHPuria case excreted large amounts of DHT and dihydrouracil, both out of the normal range.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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