DeCure's autonomous Cardio AI scientist is researching a drug-repurposing hypothesis for pulmonary valve disease — 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 modulePulmonary valve disease 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 pulmonary valve disease 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
endoglin (ENG) — ENG 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 pgedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5I04 · 2.42 Å · ligand TRIETHYLENE GLYCOL (PGE). Experimental structure, not a prediction.
What the evidence adds up to
The 2021 study on YTHDF1 and pulmonary hypertension found elevated m6A RNA modification and increased YTHDF1 protein in human and rodent PH samples and in hypoxic pulmonary artery smooth muscle cells. Deleting YTHDF1 reduced PASMC proliferation, phenotype switch, and PH development in vivo and in vitro. The m6A-regulated gene MAGED1 was identified; genetic ablation of MAGED1 improved vascular remodelling and haemodynamic parameters in SU5416/hypoxia mice. YTHDF1 promoted MAGED1 translation in an m6A-dependent manner, and MAGED1 silencing inhibited hypoxia-induced PASMC proliferation via downregulation of PCNA. The study concerns pulmonary hypertension, not pulmonary valve disease, and no drug is tested.
A 2020 review of heart valve development and disease describes complex interactions between cardiac cell types and haemodynamic forces, noting that many genetic pathways active in valve development are also implicated in diseased valves. It does not report any drug testing or clinical outcomes.
A 2020 manuscript on drug repurposing for pulmonary arterial hypertension states that repurposing has been a success story, with positive phase 3 trials for epoprostenol, bosentan, iloprost, and sildenafil. It notes that despite multiple therapies, mortality rates have changed modestly, patients remain highly symptomatic, and many end up on parenteral therapy or lung transplant waiting lists. The manuscript is a debate platform, not a trial report, and addresses PAH, not pulmonary valve disease.
A 2019 study evaluated a novel bioprosthetic pulmonary valve made from CorMatrix tissue and supported by a LactoSorb ring in an acute porcine model. In-vitro testing showed proper opening and closure at physiological haemodynamic conditions. In-vivo evaluation in pigs gave a peak right ventricular pressure of 38 mmHg, peak pulmonary artery pressure of 27 mmHg, and a peak valve gradient of 11 mmHg. The pulmonary pressure wave showed a dicrotic notch indicating valve competence. The valve was made entirely from biodegradable materials and worked acutely, but no long-term data, human data, or drug repurposing is reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
American Journal of Respiratory and Critical Care Medicine · 2021 · 128 citations
YTHDF1 Regulates Pulmonary Hypertension through Translational Control of MAGED1
AbstractAbstract Rationale Posttranscriptional modifications are implicated in vascular remodeling of pulmonary hypertension (PH). m6A (N6–methyladenosine) is an abundant RNA modification that is involved in various biological processes. Whether m6A RNA modification and m6A effector proteins play a role in pulmonary vascular remodeling and PH has not been demonstrated. Objectives To determine whether m6A modification and m6A effectors contribute to the pathogenesis of PH. Methods m6A modification and YTHDF1 expression were measured in human and experimental PH samples. RNA immunoprecipitation analysis and m6A sequencing were employed to screen m6A-marked transcripts. Genetic approaches were employed to assess the respective roles of YTHDF1 and MAGED1 in PH. Primary cell isolation and cultivation were used for function analysis of pulmonary artery smooth muscle cells (PASMCs). Measurements and Main Results Elevated m6A levels and increased YTHDF1 protein expression were found in human and rodent PH samples as well as in hypoxic PASMCs. The deletion of YTHDF1 ameliorated PASMC proliferation, phenotype switch, and PH development both in vivo and in vitro. m6A RNA immunoprecipitation analysis identified MAGED1 as an m6A-regulated gene in PH, and genetic ablation of MAGED1 improved vascular remodeling and hemodynamic parameters in SU5416/hypoxia mice. YTHDF1 recognized and promoted translation of MAGED1 in an m6A-dependent manner that was absent in METTL3-deficient PASMCs. In addition, MAGED1 silencing inhibited hypoxia-induced proliferation of PASMCs through downregulating PCNA. Conclusions YTHDF1 promotes PASMC proliferation and PH by enhancing MAGED1 translation. This study identifies the m6A RNA modification as a novel mediator of pathological changes in PASMCs and PH.
AbstractThe valves of the heart are crucial for ensuring that blood flows in one direction from the heart, through the lungs and back to the rest of the body. Heart valve development is regulated by complex interactions between different cardiac cell types and is subject to blood flow-driven forces. Recent work has begun to elucidate the important roles of developmental pathways, valve cell heterogeneity and hemodynamics in determining the structure and function of developing valves. Furthermore, this work has revealed that many key genetic pathways involved in cardiac valve development are also implicated in diseased valves. Here, we review recent discoveries that have furthered our understanding of the molecular, cellular and mechanosensitive mechanisms of valve development, and highlight new insights into congenital and acquired valve disease.
Respiratory Research · 2019 · 25 citations · open access
Silibinin efficacy in a rat model of pulmonary arterial hypertension using monocrotaline and chronic hypoxia
AbstractBACKGROUND: C-X-C chemokine receptor type 4 (CXCR4) may be involved in the development of pulmonary arterial hypertension (PAH). CXCR4 inhibitor AMD3100 was described to have a positive effect on the prevention of pulmonary arterial muscularization in PAH models. Silibinin is a traditional medicine that has an antagonistic effect on CXCR4. We investigated the effect of silibinin using rat models of PAH. METHODS: ) with or without silibinin. To evaluate the efficacy of silibinin on PAH, right ventricular systolic pressure (RVSP), Fulton index (weight ratio of right ventricle to the left ventricle and septum), percent medial wall thickness (% MT), and vascular occlusion score (VOS) were measured and calculated. Immunohistochemical analysis was performed targeting CXCR4 and c-Kit. Reverse transcription-quantitative polymerase chain reaction was performed for the stem cell markers CXCR4, stromal cell derived factor-1 (SDF-1), c-Kit, and stem cell factor (SCF), and the inflammatory markers monocyte chemoattractant protein 1 (MCP1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα). Statistical analyses were performed using t-test and one-way analysis of variance with Bonferroni's post hoc test. RESULTS: Silibinin treatment for 1 week reduced RVSP and Fulton index. Treatment for 2 weeks reduced RVSP, Fulton index, % MT, and VOS, as well as downregulating the expression of CXCR4, SDF-1, and TNFα in pulmonary arteries. In contrast, treatment for 3 weeks failed to ameliorate PAH. The time-course study demonstrated that RVSP, Fulton index, % MT, and VOS gradually increased over time, with a decrease in the expression of CXCR4 and TNFα occurring after 2 weeks of PAH development. After 3 weeks, SDF-1, c-Kit, and SCF began to decrease and, after 5 weeks, MCP1 and IL-6 gradually accumulated. CONCLUSIONS: The CXCR4 inhibitor silibinin can ameliorate PAH, possibly through the suppression of the CXCR4/SDF-1 axis, until the point where PAH becomes a severe and irreversible condition. Silibinin results in reduced pulmonary arterial pressure and delays pulmonary arteriolar occlusion and pulmonary vascular remodeling.
Pulmonary Circulation · 2020 · 13 citations · open access
Repurposing of medications for pulmonary arterial hypertension
AbstractThis manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.
Journal of Cardiothoracic Surgery · 2019 · 11 citations · open access
In-vitro and in-vivo evaluation of a novel bioprosthetic pulmonary valve for use in congenital heart surgery
AbstractBACKGROUND: Management of congenital malformations of the pulmonary artery and valve can be challenging. The severity often demands early intervention, which is rarely definitive due to the natural growth and multiple surgeries may be required. An artificial valve made entirely from biodegradable materials that will serve as a bioscaffold for host recellularization would be an attractive solution for these patients. Such valves have been experimentally evaluated with various results. In this study, a simple valve design supported by an absorbable proximal stabilization ring is evaluated both in-vitro and in-vivo. METHODS: From a 6.7 × 5.0 cm sheet of CorMatrix® tissue we created the valve as an inverted tubegraft with three sutured commissures. A non-closed ring of LactoSorb® basally supported the valve. The commissure height was 2 cm. Inserted as an interposition graft the valve was tested in an in-vitro model and an acute porcine model. Right ventricular and pulmonary artery pressures were recorded. RESULTS: The in-vitro testing indicated a proper opening and closure function of valve at physiological simulated hemodynamic conditions. The in-vivo evaluation showed a peak right ventricular pressure of 38 mmHg and a peak pulmonary artery pressure of 27 mmHg and thereby a peak valve gradient of 11 mmHg. The pulmonary pressure wave demonstrated a dicrotic notch indicating competence of the valve. CONCLUSION: This new pulmonary valve made entirely from biodegradable tissue worked in an acute setting and displayed a good hemodynamic profile. The valve gradient observed is equal to or superior of today's surgical treatment options.
Expert Opinion on Pharmacotherapy · 2005 · 11 citations
Eisenmenger syndrome: medical prevention and management strategies
AbstractThe original definition of Eisenmenger syndrome refers to an unrestrictive post-tricuspid valve congenital systemic-to-pulmonary shunt. When the pulmonary arterial systolic pressure becomes equal to the systemic arterial systolic pressure, the direction of the shunt becomes pulmonary-to-systemic. The latter leads to progressive cyanosis, and exercise intolerance is initially proportional to the degree of hypoxaemia. Later, congestive heart failure may occur . The management principle is to avoid any factors that destabilise this delicately balanced physiology. Until recently, this could only be achieved by symptomatic therapy; however, when patients are severely incapacitated, transplantation is needed. At present, new drugs, which are more selective pulmonary vasodilators, are available to interfere with the ongoing disease process to improve functional capacity and delay the decision for transplantation.
Annals of the American Thoracic Society · 2013 · 7 citations · open access
Personalized Management of Chronic Obstructive Pulmonary Disease via Transcriptomic Profiling of the Airway and Lung
AbstractChronic obstructive pulmonary disease (COPD) is a clinically heterogeneous disease composed of variable degrees of airflow obstruction, emphysematous destruction, and small airway wall thickening. The natural history of this disease, although generally characterized by continued decline in lung function, is also highly variable. Novel transcriptomic approaches to study the airway and lung tissue in COPD hold the potential to improve our understanding of the molecular mechanisms underlying this heterogeneity and identify molecular subtypes of disease that have similar clinical manifestations. This new understanding can be leveraged to develop targeted COPD therapies and ultimately personalize treatment of COPD based on each patient's specific molecular subphenotype.
The Anatolian Journal of Cardiology · 2024 · 1 citations · open access
Bioinformatic Analysis and Molecular Docking Identify Isorhamnetin Is a Candidate Compound in the Treatment of Pulmonary Artery Hypertension
AbstractBACKGROUND: The current study aims to identify the key pathways and potential therapeutic targets for pulmonary arterial hypertension (PAH) and to further evaluate the anti-PAH effects of isorhamnetin. METHODS: The dataset of gene expression profiling for PAH (GSE113439) was downloaded from the gene expression omnibus (GEO) database. Isorhamnetin target genes were extracted from the comparative toxicogenomics database (CTD). Various bioinformatics methods were employed to identify the core pathways associated with PAH and potential intervention targets. Molecular docking was conducted between the interacting target and the candidate compound, isorhamnetin. RESULTS: One thousand nine hundred sixty-two upregulated genes and 642 downregulated genes were identified. Molecular complex detection analyses revealed that the significant biological processes associated with upregulated genes included DNA damage response, mitotic cell cycle, and chromosome organization. In contrast, the signifi ant biological processes related to downregulated genes encompassed cellular response to growth factor stimulus, response to growth factor, and blood vessel development. Immune infilt ation analysis indicated that PAH is associated with signifi ant changes in the distribution of immune cells and differential expression of immune checkpoints. Furthermore, 58 isorhamnetin targets were extracted from the CTD, and we identified 1 interacting gene, NFE2L2, among the differentially expressed genes (DEGs), DEGs related to ferroptosis, and isorhamnetin targets. Isorhamnetin demonstrated strong affinities with vascular endothelial growth factor (VEGF) receptors and transcription factors (ATM and ZNF24) associated with VEGFs, as well as the ferroptosis protein NFE2L2. CONCLUSIONS: Pulmonary arterial hypertension is characterized by a series of abnormalities in downstream molecular signaling pathways, including DNA damage, immune dysregulation, VEGF signaling deficienc , and the ferroptosis process. These may represent the core pathophysiological mechanisms of PAH. Ferroptosis-related genes, such as NFE2L2 and TF (ATM, ZNF24) associated with VEGFs, are potential therapeutic targets that contribute to the mechanisms mentioned above. Isorhamnetin is a promising candidate compound for the treatment of PAH.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
