DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for fructose-1,6-bisphosphatase 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 moduleFructose-1,6-bisphosphatase 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 fructose-1,6-bisphosphatase 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
fructose-bisphosphatase 1 (FBP1) — FBP1 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 ampdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7WJV · 1.724 Å · ligand ADENOSINE MONOPHOSPHATE (AMP). Experimental structure, not a prediction.
What the evidence adds up to
The 1995 study cloned the human liver fructose-1,6-bisphosphatase gene (FBP1), localised it to chromosome bands 9q22.2-q22.3, and determined its exon-intron organisation. In two subjects with fructose-1,6-bisphosphatase deficiency, four nucleotide substitutions were identified, but all were also found in normal unaffected subjects and therefore are not the cause of the deficiency. The molecular basis in those two subjects remained undetermined.
A 2022 study performed whole-exome sequencing in an adult patient with severe hypoglycaemic lactic acidosis and identified compound heterozygous missense mutations of FBP1: c.491G>A (p.G164D) and c.581T>C (p.F194S). Biochemical analysis showed that each mutant decreased protein expression and caused enzyme activity loss. The mutants aggregated in the endoplasmic reticulum, and interactome analysis indicated involvement of unfolded protein response proteins. The authors classified all previously reported FBP1 missense mutations into three functional categories: Type 1 mutations affect enzyme activity motifs without altering protein expression; Type 2 mutations change amino acid hydrophobicity, cluster around the substrate-binding pocket, and are associated with aggregation in the endoplasmic reticulum and decreased protein expression; Type 3 mutations are likely non-pathogenic. The study concluded that protein misfolding contributes to pathogenesis, particularly for Type 2 mutations.
A 2018 review article discussed fructose-1,6-bisphosphatase inhibitors as a therapeutic target for type 2 diabetes, not for fructose-1,6-bisphosphatase deficiency. That review summarised advances in inhibitor development from 2000 to 2017.
What remains missing is any clinical trial of a drug for fructose-1,6-bisphosphatase deficiency. No therapy has been tested in patients with this disorder. The 2022 study suggests that protein misfolding may be a targetable mechanism for some mutations, but no compound has been evaluated in that context. Funding for drug development in this ultra-rare disease, and a trial design that accounts for the small number of patients and the need for genotype stratification, are absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Genomics · 1995 · 78 citations · open access
Human Fructose-1,6-Bisphosphatase Gene (FBP1): Exon-Intron Organization, Localization to Chromosome Bands 9q22.2-q22.3, and Mutation Screening in Subjects with Fructose-1,6-Bisphosphatase Deficiency
AbstractFructose-1,6-bisphosphatase (EC 3.1.3.11) is a key regulatory enzyme of gluconeogenesis that catalyzes the hydrolysis of fructose-1,6-bisphosphate to generate fructose-6-phosphate and inorganic phosphate. Deficiency of fructose-1,6-bisphosphatase is associated with fasting hypoglycemia and metabolic acidosis because of impaired gluconeogenesis. We have cloned and characterized the human liver fructose-1,6-bisphosphatase gene (FBP1). FBP1, localized to chromosome bands 9q22.2-q22.3 by fluorescence in situ hybridization, consists of seven exons that span > 31 kb, and the six introns are in the same position as in the rat gene. FBP1 was screened for mutations in two subjects with fructose-1,6-bisphosphatase deficiency. Four nucleotide substitutions were identified, two of which were silent mutations in the codons for Ala-216 (GCT-->GCC) and Gly-319 (GGG-->GGA). The other substitutions were in intron 3, a C-->T substitution 7 nucleotides downstream from the splice donor site, and in the promoter region, an A-->T substitution 188 nucleotides upstream from the start of transcription. These nucleotide substitutions were also found in normal unaffected subjects and thus are not the cause of fructose-1,6-bisphosphatase deficiency in the two subjects studied. The molecular basis of hepatic fructose-1,6-bisphosphatase deficiency in these subjects remains undetermined but could result from unidentified mutations in the promoter that decrease expression or from mutations in another gene that indirectly lead to decreased fructose-1,6-bisphosphatase activity.
Fructose-1,6-bisphosphatase Inhibitors: A Review of Recent (2000- 2017) Advances and Structure-Activity Relationship Studies
AbstractDiabetes mellitus, commonly referred to as diabetes, is the 8th leading cause of death worldwide. As of 2015, approximately 415 million people were estimated to be diabetic worldwide, type 2 diabetes being the most common accounting for approximately 90-95% of all diagnosed cases with increasing prevalence. Fructose-1,6-bisphosphatase is one of the important therapeutic targets recently discovered to treat this chronic disease. In this focused review, we have highlighted recent advances and structure-activity relationship studies in the discovery and development of different fructose-1,6-bisphosphatase inhibitors reported since the year 2000.
Research Square · 2022 · 0 citations · open access
Characterization based on genotype–biochemical phenotype association in fructose-1,6-bisphosphatase deficiency
AbstractAbstract Purpose Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. The mechanism by which the mutations cause enzyme activity loss is uncertain. Methods We performed whole-exome sequencing in an adult patient with severe hypoglycemic lactic acidosis and identified that the patient carried compound heterozygous missense mutations of FBP1 with c.491G > A (p.G164D) and c.581T > C (p.F194S). Results Biochemical analysis revealed that FBP1 mutant (G164D or F194S) decreased protein expression and enzyme activity loss. The interactome analysis for binding partners demonstrated that G164D and F194S mutants interact with the proteins involved in unfolded protein response. Additionally, G164D and F194S mutants aggregated in the endoplasmic reticulum, suggesting the involvement of protein misfolding in its pathogenesis. All FBP1 missense mutations previously reported were classified into three functional categories: Type 1 mutations, located at pivotal residues in enzyme activity motifs with no effects on protein expression; Type 2 mutations, which mediate changes in amino acid hydrophobicity and structurally cluster around the substrate-binding pocket, are associated with aggregation in the endoplasmic reticulum, and decreased protein expression; and Type 3 mutations, which are likely non-pathogenic mutations. Conclusion Protein misfolding contributes to FBPase deficiency pathogenesis, particularly in Type 2 mutations.
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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