DeCure for Dihydropyrimidine dehydrogenase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for dihydropyrimidine dehydrogenase deficiency — 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 moduleDihydropyrimidine dehydrogenase deficiency 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 dihydropyrimidine dehydrogenase deficiency 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.
What the evidence adds up to
Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive disorder of pyrimidine metabolism. The enzyme DPD catalyses the first and rate-limiting step in the catabolism of uracil, thymine, and the chemotherapeutic drug 5-fluorouracil. More than 30 patients had been diagnosed with complete enzyme deficiency by 2005. One patient described in 2005, the fifth case presenting at birth with severe neurological abnormalities, was homozygous for the common splice-site mutation IVS14+1G>A. A 2010 case presented with convulsions, psychomotor retardation, and Reye-like syndrome, with strongly elevated uracil and thymine in urine and no detectable DPD activity in peripheral blood mononuclear cells; that patient was homozygous for a novel c.505_513del (p.169_171del) mutation in exon 6 of DPYD.
Three novel mutations were identified in 2005 from two patients with complete DPD deficiency and the parents of an affected child. One was a splice site mutation, IVS11+1G>T, which created a cryptic splice site in exon 11 and caused a 141-base-pair fragment encoding amino acid residues 400–446 to be missing from the mature mRNA. Two missense mutations were also found: 731A>C (E244V), which structural analysis of pig DPD suggested might interfere with electron flow between NADPH and the pyrimidine binding site, and 1651G>A (A551T), which might prevent binding of the prosthetic group FMN and affect protein folding. These mutations were identified to allow recognition of patients at increased risk of severe 5-fluorouracil-associated toxicity.
No treatment or intervention for DPD deficiency itself is described in these abstracts. The reports are limited to genetic and biochemical characterisation of individual patients. What is missing is any clinical trial of a therapy, any systematic patient registry with standardised outcome measures, any funding for drug development, and any stratification of patients by residual enzyme activity or specific mutation type that might guide future attempts at intervention.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Biological Chemistry · 2005 · 27 citations
Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function
AbstractDihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine, as well as of the widely used chemotherapeutic drug 5-fluorouracil (5FU). Analysis of the DPD gene ( DPYD ) in two patients presenting with complete DPD deficiency and the parents of an affected child showed the presence of three novel mutations, including one splice site mutation IVS11 + 1G-->T and the missense mutations 731A-->C (E244V) and 1651G-->A (A551T). The G-->T mutation in the invariant GT splice donor site flanking exon 11 (IVS11 + 1G-->T) created a cryptic splice site within exon 11. As a consequence, a 141-bp fragment encoding the aminoacid residues 400-446 of the primary sequence of the DPD protein was missing in the mature DPD mRNA. Analysis of the crystal structure of pig DPD suggested that the E244V mutation might interfere with the electron flow between NADPH and the pyrimidine binding site of DPD. The A551T point mutation might prevent binding of the prosthetic group FMN and affect folding of the DPD protein. The identification of these novel mutations in DPYD will allow the identification of patients with an increased risk of developing severe 5FU-associated toxicity.
Journal of Inherited Metabolic Disease · 2005 · 15 citations
Dihydropyrimidine dehydrogenase deficiency presenting at birth
AbstractDihydropyrimidine dehydrogenase (DPD) deficiency (McKusick 274270) is a clinically heterogeneous autosomal recessive disorder of pyrimidine metabolism. DPD is the enzyme that catalyses the first and the rate-limiting step in the catabolism of uracil, thymine and the analogue 5-fluorouracil. To date, more than 30 patients have been diagnosed with a complete enzyme deficiency. Here, we describe the fifth case with a complete DPD deficiency presenting at birth with severe neurological abnormalities. The patient was homozygous for the common splice-site mutation IVS14+1G > A.
Dihydropyrimidine Dehydrogenase Deficiency Caused by a Novel Genomic Deletion c.505_513del of<i>DPYD</i>
AbstractDihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine degradation pathway. In a patient presenting with convulsions, psychomotor retardation and Reye like syndrome, strongly elevated levels of uracil and thymine were detected in urine. No DPD activity could be detected in peripheral blood mononuclear cells. Analysis of the gene encoding DPD (DPYD) showed that the patient was homozygous for a novel c.505_513del (p.169_171del) mutation in exon 6 of DPYD.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
