DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Brugada syndrome 1 — screening already-approved drugs against its 11-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleBrugada syndrome 1 maps to a 11-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 brugada syndrome 1 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
sodium voltage-gated channel beta subunit 1 (SCN1B) — SCN1B 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…
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RCSB Protein Data Bank · entry 7W9K · 2.2 Å · ligand O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine (P5S). Experimental structure, not a prediction.
What the evidence adds up to
In 10 unrelated Brugada probands, right-ventricular biopsies showed a distinct ion-channel expression pattern compared to non-diseased donors, heart-transplant recipients, and patients with other ventricular arrhythmias. Nav1.5, Kv4.3, and Kir3.4 were more weakly expressed, while Nav2.1 and TWIK1 were more strongly expressed. Differences also appeared in calcium-handling transcripts, with stronger expression of RYR2 and NCX1. The molecular profile did not differ between Brugada patients with SCN5A mutations and those without.
As of 2010, all known genetic defects together explained only 30% of cases. Despite the discovery of the first genetic defect in 1998 and additional mutations and a common variant described in 2009, the genetic basis of the syndrome remained largely unknown. A 2021 study of 100 Brugada patients from Henan, China, found that 60 carried DSG2 gene variants, 50 carried TTN gene variants, and 20 carried GATA4 gene variants. All 100 patients had ventricular arrhythmia on ECG; 87% had ventricular tachycardia, 84% had T-wave inversion, and 51% had Epsilon wave. Echocardiography showed right-ventricular enlargement (mean inner diameter 40.0 mm), abnormal right-ventricular systolic function, right-atrial enlargement in 64%, and left-ventricular involvement in 27%.
The diagnostic criterion—type 1 Brugada ECG pattern—remains mandatory, and historical confusion with other entities has been noted. No drug intervention was tested in any of these studies. What is still missing is a therapy that modifies the ion-channel expression signature or the genetic variants identified, along with prospective trials that stratify patients by molecular or genetic subtype.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
European Heart Journal · 2008 · 57 citations · open access
Transcriptional profiling of ion channel genes in Brugada syndrome and other right ventricular arrhythmogenic diseases
AbstractAIMS: Brugada syndrome is an inherited sudden-death arrhythmia syndrome. Na(+)-current dysfunction is central, but mutations in the SCN5A gene (encoding the cardiac Na(+)-channel Nav1.5) are present in only 20% of probands. This study addressed the possibility that Brugada patients display specific expression patterns for ion-channels regulating cardiac conduction, excitability, and repolarization. METHODS AND RESULTS: Transcriptional profiling was performed on right-ventricular endomyocardial biopsies from 10 unrelated Brugada probands, 11 non-diseased organ-donors, seven heart-transplant recipients, 10 with arrhythmogenic right-ventricular cardiomyopathy, and nine with idiopathic right-ventricular outflow-tract tachycardia. Brugada patients showed distinct clustering differences vs. the two control and two other ventricular-tachyarrhythmia groups, including 14 of 77 genes encoding important ion-channel/ion-transporter subunits. Nav1.5 and K(+)-channels Kv4.3 and Kir3.4 were more weakly expressed, whereas the Na(+)-channel Nav2.1 and the K(+)-channel TWIK1 were more strongly expressed, in Brugada syndrome. Differences were also seen in Ca(2+)-homeostasis transcripts, including stronger expression of RYR2 and NCX1. The molecular profile of Brugada patients with SCN5A mutations did not differ from Brugada patients without SCN5A mutations. CONCLUSION: Brugada patients exhibit a common ion-channel molecular expression signature, irrespective of the culprit gene. This finding has potentially important implications for our understanding of the pathophysiology of Brugada syndrome, with possible therapeutic and diagnostic consequences.
Current Opinion in Cardiology · 2010 · 38 citations
Genetics of Brugada syndrome
AbstractPURPOSE OF REVIEW: The Brugada syndrome has been investigated in depth since its description in 1992 both on a clinical and on a basic research level. Since the discovery of the first genetic defect in 1998, several genes have been subsequently identified. However, to date all these genes together explain only 30% of the cases, indicating that there is still an important amount of work to be done to totally unravel the genetic basis of this lethal disease. In the present study, we will focus on recent achievements in the genetic basis of this disease. RECENT FINDINGS: In 2009, several additional genetic mutations have been associated with the disease. Additionally, a common variant has been described as a genetic modulator of Brugada syndrome among carriers of a SCN5A mutation. SUMMARY: The number of scientific publications dealing with the syndrome has continued to increase substantially in recent years. New polymorphisms, mutations and genes associated with the disease have been described. However, despite the advances, knowledge of the genetic determinants of the Brugada syndrome remains limited.
Journal of Human Growth and Development · 2020 · 4 citations · open access
The numerous denominations of the Brugada syndrome and proposal about how to put an end to an old controversy - a historical-critical perspective
AbstractBackgroung: The eponymous Brugada Syndrome (BrS) in honor of its discovery as an independent entity by the Spanish/ Catalan Brugada brothers, Pedro and Josep, has deserved numerous denominations derived mainly from the clinical genotype/phenotype correlation. The purpose of this manuscript is to present and analyze the nomenclatures that this intriguing and challenging syndrome has received over the past 28 years. We also compared the main features between cases from the first report of the Brugada brothers and an article by Martini et al. The nomenclatures used by these authors are closely linked to the BrS, but the cases (except one) presented in the article by Martini et al do not present the type 1 Brugada ECG pattern, which is mandatory for the diagnosis of BrS.
[Analysis of DSG2, TTN and GATA4 gene variants in patients with Brugada syndrome from Henan].
AbstractOBJECTIVE: To explore the correlation between DSG2, TTN and GATA4 genes and Brugada syndrome in Henan Province of China. METHODS: From February 2017 to February 2019, 100 patients with Brugada syndrome and 100 healthy individuals were selected as the study and the control groups, respectively. Electrocardiogram and echocardiography were carried out, and peripheral blood samples was collected. Coding regions of DSG2, TTN and GATA4 genes were amplified by PCR and sequenced. The results were compared with standard sequences from GenBank. RESULTS: Electrocardiogram showed that all patients from the study group had ventricular arrhythmia, 87 cases (87%) presented ventricular tachycardia (VT), 84 cases (84%) presented T wave inversion, and 51 cases (51%) presented Epsilon wave. Echocardiography showed that the right ventricle in the study group was enlarged with the inner diameter of the right ventricle being (40.0±13.3) mm, and the right ventricle showed various degree of abnormal systolic function. The enlargement of right atrium accounted for 64%, and the involvement of the left ventricle accounted for 27%. The right ventricular diameter and left ventricular diastolic diameter of the study group were significantly greater than those of the control group (P< 0.05). DNA sequencing showed that 60 patients carried DSG2 gene variants, among which 18 had missense variant of exon 8. Fifty patients carried TTN gene variants, including 8 in the A-band domain and 3 in the I-band domain. Twenty patients carried 3 variants of the GATA4 gene. CONCLUSION: Variants of the DSG2, TTN and GATA4 genes in Henan region are correlated with the onset of Brugada syndrome.
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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