DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for C1 inhibitor 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 moduleC1 inhibitor 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 c1 inhibitor 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
serpin family G member 1 (SERPING1) — SERPING1 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 so3drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5DUQ · 2.9 Å · ligand SULFITE ION (SO3). Experimental structure, not a prediction.
What the evidence adds up to
A 1993 study identified a mutation in the C1-inhibitor gene, Ala436 to Thr at the P10 position of the hinge region, in two kindred with type II hereditary angioedema. The mutant protein, called C1-inhibitor(Mo), lost its inhibitory activity but, unlike other hinge region mutations, was not converted to a substrate. Instead it polymerised, existing in both monomeric and multimeric forms, likely by reactive centre loop insertion into the A sheet of an adjacent molecule. Native C1-inhibitor(Mo) had a thermal stability profile intermediate between intact and cleaved normal C1-inhibitor, and its conformation resembled the complexed form of normal C1-inhibitor.
A 1995 paper described a different mutation, Ala443 to Val at the P2 residue, in a large kindred with an unusual C1 inhibitor abnormality but without angioedema. Affected members were heterozygous: half their serum C1 inhibitor molecules were normal, the other half complexed with C1s but showed little complex formation with C1r and were relatively resistant to trypsin digestion. Recombinant Ala443-->Val mutant, expressed in COS-1 cells, complexed completely with C1s, kallikrein, and coagulation Factor XIIa after 60 minutes at 37°C, but failed to complex completely with C1r under the same conditions. The rate of complex formation with C1s was also impaired. The mutant converted C1 inhibitor from a substrate to an inhibitor of trypsin, a serine protease that normally cleaves wild-type C1 inhibitor.
An earlier 1988 study showed that full-length human C1 inhibitor cDNA could be expressed in COS-1 cells. The secreted recombinant protein had a molecular weight of approximately 110,000, formed SDS-stable complexes with C1s, factor XIIa, and kallikrein, inhibited C1s-mediated C4 consumption, and was inactivated by elastase. The level of recombinant C1 inhibitor reached approximately 2.2 micrograms per ml 72 hours after transfection. Treatment with tunicamycin produced a protein of approximately 90,000 that still formed complexes with C1s.
What is still missing is any clinical trial data for a drug repurposed in C1 inhibitor deficiency. These studies are limited to in vitro and recombinant protein work on specific mutations, with no patient-level outcomes, no survival or response rates, and no evidence that any existing drug alters the course of hereditary angioedema. A repurposing effort would need funding for a properly designed trial, and likely require patient stratification by mutation type, since the functional consequences of different mutations vary substantially.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Biological Chemistry · 1993 · 111 citations · open access
A hinge region mutation in C1-inhibitor (Ala436–>Thr) results in nonsubstrate-like behavior and in polymerization of the molecule.
AbstractC1-inhibitor(Mo), a dysfunctional C1-inhibitor molecule produced in two kindred with type II hereditary angioedema, has a mutation at the P10 position (Ala436 to Thr). Like most serpins with hinge region mutations (P14, P12, P10), C1-inhibitor(Mo) loses its inhibitory activity. However, unlike the other hinge region mutations, this mutant is not converted to a substrate. As shown by nondenaturing gel electrophoresis, gel filtration, sucrose density gradient ultracentrifugation, and electron microscopy, C1-inhibitor(Mo) exists in both monomeric and multimeric forms. Polymerization probably results from reactive center loop insertion into the A sheet of an adjacent molecule. Native C1-inhibitor(Mo) was shown to have a thermal stability profile intermediate to those of intact and of cleaved normal C1-inhibitor. Native C1-inhibitor(Mo) did not bind to monoclonal antibody KII, which binds only to reactive center-cleaved normal C1-inhibitor. It did, however, react with monoclonal antibody KOK12, which recognizes complexed or cleaved C1-inhibitor but not intact normal C1-inhibitor. Native C1-inhibitor(Mo), therefore, exists in a conformation similar to the complexed form of normal C1-inhibitor.
Journal of Clinical Investigation · 1995 · 64 citations · open access
Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein.
AbstractWe have determined the cause of an unusual C1 inhibitor abnormality in a large kindred. We previously found that half of serum C1 inhibitor molecules in affected kindred members are normal. The other half complexed with C1s but showed little complex formation with C1r. These molecules also appeared to be relatively resistant to digestion by trypsin. Taken together, the findings suggested that members of this kindred are heterozygous for an unusual C1 inhibitor mutation. Sequencing of genomic DNA from the kindred revealed that thymine has replaced cytosine in the codon for Ala443 (P2 residue) in one C1 inhibitor allele, resulting in substitution with a Val residue. To test the effect of this substitution, a mutant C1 inhibitor containing Ala443-->Val was constructed by site-directed mutagenesis and expressed in COS-1 cells. Both the Ala443-->Val mutant and the wild-type C1 inhibitor complexed completely with C1s, kallikrein, and coagulation Factor XIIa after incubation at 37 degrees C for 60 min. In contrast, the mutant inhibitor failed to complex completely with C1r under the same conditions. Time course analysis showed that the ability of the mutant to complex with C1s is also impaired: although it complexed completely in 60 min, the rate of complex formation during a 0-60-min incubation was decreased compared with wild-type C1 inhibitor. The mutant inhibitor also formed a complex with trypsin, a serine protease that cleaves, and is not inhibited by, wild-type C1 inhibitor. The Ala443-->Val mutation therefore converts C1 inhibitor from a substrate to an inhibitor of trypsin. These studies emphasize the role of the P2 residue in the determination of target protease specificity.
Journal of Biological Chemistry · 1988 · 43 citations · open access
Expression of functional human C1 inhibitor in COS cells.
AbstractFull length human C1 inhibitor cDNA was cloned into a vector suitable for transient expression in COS-1 cells. Transfected COS cells secreted an immunoreactive protein of Mr approximately 110,000 that appeared to be functionally equivalent to the plasma-derived protein as established by the following criteria: 1) ability to form sodium dodecyl sulfate-stable complexes with C1s, factor XIIa, and kallikrein; 2) inhibition of C1s-mediated C4 consumption; and 3) susceptibility to inactivation by the nontarget proteinase elastase. Quantitation of secreted recombinant C1 inhibitor by radioimmunoassay indicated that 72 h after transfection the level was approximately 2.2 micrograms/ml. Treatment of transfected cells with tunicamycin resulted in secretion of a protein of Mr approximately 90,000 that was also capable of complex formation with C1s.
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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