DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for d-bifunctional protein deficiency — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleD-bifunctional protein deficiency maps to a 2-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 d-bifunctional protein 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.
Molecular view
hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) — HSD17B4 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 naddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1ZBQ · 2.19 Å · ligand NICOTINAMIDE-ADENINE-DINUCLEOTIDE (NAD). Experimental structure, not a prediction.
What the evidence adds up to
D-bifunctional protein deficiency is a rare autosomal recessive peroxisomal enzyme deficiency that causes severe morbidity and early mortality. Patients typically present with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, and blindness, with death usually within the first two years of life, though those with residual enzyme function can survive longer. A 2021 case report of a full-term newborn with hypotonia, seizures, and unexplained hypoglycaemia later found to have rickets used rapid whole genome sequencing to identify two HSD17B4 variants in trans. RNA-seq from the father showed skipping of exon 14, producing a frameshift mutation, and this correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants were reclassified as pathogenic. The report adds persistent hypoglycaemia to the clinical spectrum and advocates early management of fat-soluble vitamin deficiencies to reduce complications.
A 2009 study used structure-function analysis and clinical data to establish a genotype-phenotype correlation for D-bifunctional protein deficiency, noting that a milder form with expanded lifespan occurs in patients carrying certain mutations. The study tested mutant MFE-2 variants (T15A, N158D, E232K, R248C, W249G) for stability and reversal of folding defects using urea and guanidinium chloride denaturation monitored by tryptophan fluorescence, thermal stability measured by CD spectroscopy, and chemical or pharmacological chaperone screening. All variants were expressed as recombinant proteins and purified, and preliminary stability results were obtained, but no chaperone or drug that rescues function in patients was reported.
No clinical trial of any drug for D-bifunctional protein deficiency has been published. The 2009 work is limited to in vitro protein studies, and the 2021 case report describes only diagnosis and supportive care. What is missing is funding for preclinical chaperone screening in patient-derived cell lines, a properly designed trial to test any identified stabiliser in humans, and stratification of patients by residual enzyme activity, since the disease severity depends on the degree of enzyme deficiency.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PubMed · 2011 · 10 citations
[Clinical and biochemical characteristics of predialysis patients in terms of 25 hydroxy vitamin D levels].
AbstractINTRODUCTION: Decreased levels of 25 hydroxyvitamin D (25[OH]D) have been reported in patients with chronic kidney disease (CKD). The pleiotropic effects of vitamin D are known to go beyond mineral metabolism. OBJECTIVES: The aims of this study were to: 1) Determine the 25(OH)D levels in predialysis outpatients. 2) Find out the clinical and biochemical characteristics of patients with 25(OH)D deficiency, and predictive factors for the deficiency. PATIENTS AND METHODS: An observational study in 79 predialysis outpatients was performed. Clinical and biochemical parameters were analysed in terms of nutrition, inflammation and mineral metabolism in relation to serum levels of 25(OH)D. Levels of 25(OH)D lower than 15ng/ml were considered to be deficient. RESULTS: Serum levels of 25(OH)D were deficient in 41 patients (52%). The comparative study regarding levels of vitamin 25(OH)D showed the group of patients with a deficiency, i.e. those with less than 15ng/ml, were older (70 ± 11.97 vs. 61 ± 14.5; p = 0.005), had a greater body mass index, BMI, (30±4.06 vs. 27.1 ± 5.08; p = 0.003) and increased proteinuria (1.42g/24h (0.53-2.96) vs. 0.51 (0.20-1.48), p = 0.009). This group included a greater number of diabetic patients: 20 (76.9%) vs. 6 (23%), p = 0.002. They had a higher level of parathyroid hormone (PTH): 359 (239-658) vs. 233 (129-323), p = 0.000; and more patients were under treatment with Calcitriol: 28 (62.2%) vs. 17 (37.8%), p = 0.024. In the multivariate analysis, high levels of PTH (OR 13.38; CI 95% [2.94-60.89]; p=0.001), increased proteinuria (OR 4.41; CI 95% [1.12-17.25]; p = 0.033); and being diabetic (OR 5.713; CI 95% [1.43-22.77]; p = 0.014) were independent predictor factors for patients with 25(OH)D deficiency. CONCLUSIONS: In our study, we observed a high prevalence of 25(OH)D deficiency among patients with CKD. The increased levels of PTH, the increase of proteinuria and the presence of diabetes were independent predictors for 25(OH)D deficiency.
American Journal of Medical Genetics Part A · 2021 · 8 citations · open access
D‐bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia
AbstractD-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient's father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.
Acta Crystallographica Section A Foundations of Crystallography · 2009 · 0 citations · open access
Molecular basis of D-bifunctional protein deficiency
AbstractStructure-function studies and clinical data were used to establish a genotype-phenotype correlation for D-bifunctional protein deficiency, a metabolic syndrome resulting from nonfunctional or residually active multifunctional enzyme type 2 (MFE-2) of peroxisomal fatty acyl -oxidation in humans [1]. A milder form of the disease associated with expanded life time is apparent in patients carrying certain types of mutations. We are testing mutant MFE-2 variants for their stability and reversal of the stability/folding defect. Methods include urea and guanidinium chloride denaturation monitored with tryptophan fluorescence, thermal stability measured with CD spectroscopy, and chemical or pharmacological chaperone screening. Enzyme activities are determined, and results correlated with the known crystal structure and properties of the wild-type protein. Mutant proteins are also subject to crystallization trials. Mutant proteins under study are T15A, N158D, E232K, R248C, W249G, which based on the available structural information are expected to be rather folding or stability defective than inactivated through substrate binding or catalytic site effects. All of these variants have been expressed as recombinant proteins and purified. Preliminary results on stability have been obtained. Latest results on stability and structural studies will be presented.
Acta Crystallographica Section A Foundations of Crystallography · 2009 · 0 citations · open access
Structural bases for the selection of a public TCR against the HCMV NLV epitope
AbstractStructure-function studies and clinical data were used to establish a genotype-phenotype correlation for D-bifunctional protein deficiency, a metabolic syndrome resulting from nonfunctional or residually active multifunctional enzyme type 2 (MFE-2) of peroxisomal fatty acyl -oxidation in humans [1]. A milder form of the disease associated with expanded life time is apparent in patients carrying certain types of mutations. We are testing mutant MFE-2 variants for their stability and reversal of the stability/folding defect. Methods include urea and guanidinium chloride denaturation monitored with tryptophan fluorescence, thermal stability measured with CD spectroscopy, and chemical or pharmacological chaperone screening. Enzyme activities are determined, and results correlated with the known crystal structure and properties of the wild-type protein. Mutant proteins are also subject to crystallization trials. Mutant proteins under study are T15A, N158D, E232K, R248C, W249G, which based on the available structural information are expected to be rather folding or stability defective than inactivated through substrate binding or catalytic site effects. All of these variants have been expressed as recombinant proteins and purified. Preliminary results on stability have been obtained. Latest results on stability and structural studies will be presented.
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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