DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for alpha-2-plasmin 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 moduleAlpha-2-plasmin 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 alpha-2-plasmin 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.
What the evidence adds up to
Hereditary alpha-2-plasmin inhibitor deficiency is caused by a trinucleotide deletion in exon VII of the gene, deleting Glu137, as identified in a single homozygous individual and affected family members. Transient expression of this mutant in COS-7 cells showed that most of the synthesised protein is retained inside the cells in an endoglycosidase H-sensitive form, with only a small portion secreted as a neuraminidase-sensitive form. The authors concluded that the Glu137 deletion blocks intracellular transport from the endoplasmic reticulum to the Golgi complex, leading to the deficiency.
No clinical trial of a drug for alpha-2-plasmin inhibitor deficiency itself has been reported in these abstracts. The 2023 study concerns plasminogen, human-tvmh, a replacement therapy for type 1 plasminogen deficiency, a different condition. In that open-label phase 2/3 study, 15 subjects received intravenous plasminogen, human-tvmh for up to 124 weeks. All 11 subjects with visible lesions at baseline showed at least 50% improvement after 48 weeks, and all subjects achieved a trough plasminogen activity increase of at least 10% above baseline through week 12. The dose was 6.6 mg/kg every 2–5 days for 48 weeks, then every 1–7 days. The drug received marketing approval on June 21, 2021.
The remaining abstracts describe basic mechanisms of plasmin inhibition. In 15 DIC patients, alpha-2-antiplasmin levels measured immunologically and by chromogenic substrate did not correlate when plasmin-antiplasmin complex was present. Alpha-2-macroglobulin levels were normal in most of these patients. Epsilon aminocaproic acid and salicylic acid derivatives inhibited plasminogen activation by urokinase competitively in a one-stage assay; alpha-2-macroglobulin and antithrombin III did not. The 1987 study found that the reaction between plasmin and alpha-2-macroglobulin followed second-order kinetics with a rate constant of 1.8 × 10⁵ M⁻¹ s⁻¹, unaffected by epsilon aminocaproic acid or histidine-rich glycoprotein. The authors predicted that when plasmin’s lysine binding sites are occupied, alpha-2-macroglobulin would compete effectively with alpha-2-plasmin inhibitor.
What is still missing is any clinical trial of a drug specifically for hereditary alpha-2-plasmin inhibitor deficiency. No replacement therapy, gene therapy, or small molecule has been tested in patients with this mutation. The only approved replacement product is for plasminogen deficiency, a separate disease. A trial would require patient identification, funding, and a design that accounts for the rarity of the condition and the need for a measurable endpoint such as bleeding episodes or fibrinolytic activity.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Biochemical Journal · 1980 · 130 citations · open access
Affinity-chromatographic purification of human α2-antiplasmin
AbstractA new simple and efficient purification method for alpha 2-antiplasmin is described that is based on the interaction between alpha 2-antiplasmin and a fragment from elastase-digested plasminogen constituting the three N-terminal triple-loop structures in the plasmin A-chain (LBSI). After a single-step adsorption of the alpha 2-antiplasmin from plasminogen-depleted plasma to LBSI-Sepharose and elution with 6-aminohexanoic acid, an 80-90% pure preparation with a yield of 50-60% is obtained. The major impurity is fibrinogen, which can easily be removed by gel filtration, and, as a result, a homogeneous fully active alpha 2-antiplasmin preparation is obtained that has the same properties as previously described for alpha 2-antiplasmin. Evidence is put forward that a form of alpha 2-antiplasmin with less affinity for the lysine-binding sites in plasminogen may exist, even in unfractionated plasma.
Journal of Biological Chemistry · 1989 · 39 citations · open access
Hereditary α2-plasmin inhibitor deficiency caused by a transport-deficient mutation (α2-PI-Okinawa)
Abstractalpha 2-Plasmin inhibitor is the most important physiological inhibitor of fibrinolysis; hence, its deficiency results in a severe hemorrhagic diathesis. We have cloned and characterized a mutant alpha 2-plasmin inhibitor gene from an individual homozygous for the deficiency. By sequencing all the coding exons and exon-intron boundaries of the gene, a trinucleotide deletion in exon VII that results in deletion of Glu137 was identified. We have designated this variant as alpha 2-plasmin inhibitor Okinawa. Using DNA samples amplified with the polymerase chain reaction, hybridization analysis by oligonucleotide probes confirmed the presence of this mutation in all the affected family members, including both parents. To elucidate the mechanism by which this mutation leads to the deficiency, a eukaryotic expression plasmid for alpha 2-plasmin inhibitor containing this mutation was constructed and transfected into COS-7 cells for transient expression analysis. Immunoprecipitation analysis and enzyme-linked immunosorbent assay revealed that the mutant alpha 2-plasmin inhibitor synthesized is mostly retained within the cells as an endoglycosidase H-sensitive form, and only a small portion of it is secreted into the medium as a neuraminidase-sensitive form. These results suggest that the Glu137 deletion leads to the alpha 2-plasmin inhibitor deficiency by causing a block in its intracellular transport from the endoplasmic reticulum to the Golgi complex.
Plasminogen, human‐tvmh for the treatment of children and adults with plasminogen deficiency type 1
AbstractAIM: An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted. Interim data was previously reported. The final data on 15 subjects who completed the study up to a maximum of 124 weeks are reported here. METHODS: The primary objectives were to evaluate efficacy of plasminogen replacement therapy on clinically evident or visible lesions during 48 weeks of dosing and to achieve an increase in trough plasminogen activity levels by at least an absolute 10% above baseline during 12 weeks of treatment. RESULTS: The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non-visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human-tvmh. All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12. Plasminogen, human-tvmh at a dose of 6.6 mg/kg administered every 2-5 days for 48 weeks and every 1-7 days for up to 124 weeks was well tolerated. CONCLUSION: This study provides additional evidence regarding the long-term safety and clinical utility of replacement therapy with human plasminogen for the treatment of children and adults with type 1 plasminogen deficiency. Plasminogen, human-tvmh received marketing approval on June 4, 2021. This trial was registered at www. CLINICALTRIALS: gov as #NCT02690714.
Functional Activities and Concentrations of Plasmin Inhibitors in Normal Subjects and D. I. C. Patients
AbstractAlpha-2-macroglobulin and fast antiplasmin, the main inhibitors of the fibrinolytic system, and the presence of plasmin-antiplasmin complex (P-AP) were studied in 15 DIC patients and in 20 healthy individuals. There was a lack of correlation between immunological and chromogenic substrates alpha-2 antiplasmin levels when P-AP complex were found in DIC patients (in 6/15 cases). The levels of alpha-2-macroglobulin were within the normal range in most of these patients, confirm the secondary role of this inhibitor in fibrinolysis.
A Method to Study Inhibitors of Plasminogen Activation
AbstractSummary A method to study inhibitors of plasminogen activation is described. It is mainly thought to be a one-stage plasminogenolytic method. The same type of inhibition is found in this one-stage assay system and in a two-stage caseinolytic assay system when epsilon aminocaproic acid and salicylic acid derivatives are investigated in parallel in both assay systems. Epsilon aminocaproic acid and salicylic acid derivatives inhibit the activation of plasminogen by urokinase in a competitive way. Alpha2-macroglobulin and antithrombin III did not inhibit the activation of plasminogen by urokinase.
INTERACTION OF PLASMIN WITH ALPHA-2 MACROGLOBULIN (α2 M): EFFECT OF ANTIFIBRINOLYTIC AGENTS
AbstractHarpel (Harpel, P.C. (1981) J. Clin. Invest 68, 46-55) reported that levels of α2M-plasmin complexes are elevated in patients receiving urokinase. He found that the distribution of plasmin between the two inhibitors, α2M and α2-plasmin inhibitor (α2PI) is dependent upon whether plasmin is added directly to plasma, or whether plasminogen in plasma is activated to plasmin by urokinase. In order to investigate possible mechanisms regulating the distribution of plasmin between these two inhibitors, a study was initiated to examine the effects of antifibrinolytic agents on the reaction of plasmin with α2M. The kinetics of the reaction were measured by monitoring conformational changes in the inhibitor resulting from exomplex formation. In order to minimize nonspecific proteolysis of the inhibitor by plasmin, the reaction was performed under conditions where the concentration of α2M was greater than that of the enzyme. The reaction between Lys77-plasmin and α2M followed second order kinetics with a rate constant of 1.8 X 105M-1 s-1. This rate was not affected 1 mM EACA or by 10 uM histidine rich glycoprotein (HRG). Further, it was found that the rate of Val442-plasmin was essentially the same as that found for Lys77-plasmin. Therefore, the binding of these ligands to the lysine binding sites of plasmin do not affect the association rate between plasmin and α2M. This is in contrast to the reaction of plasmin with α2-PI, where the binding of ligands to the lysine binding sites of plasmin reduce the rate of the reaction (Petersen & Clerrmensen (1981) Biochem. J. 199, 121-127). The kinetic constants measured predict that under conditions when the lysine binding sites of plasmin are occupied, α2M will effectively compete with α2PI in inhibiting plasmin. Further, these studies inplicate HRG as a molecule capable of regulating the distribution of plasmin between these two inhibitors.
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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