DeCure for Obesity due to prohormone convertase I deficiency
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for obesity due to prohormone convertase I deficiency — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleObesity due to prohormone convertase I deficiency maps to a 2-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 obesity due to prohormone convertase i 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
proprotein convertase subtilisin/kexin type 1 (PCSK1) — PCSK1 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9FIC · 1.3 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A 2006 study of a novel Pc1 mouse allele (N222D) produced obesity, hyperphagia, and increased metabolic efficiency, with defective proinsulin processing leading to glucose intolerance but not insulin resistance or diabetes. The obesity was linked to impaired autocatalytic activation of mature PC1 and reduced hypothalamic alpha-MSH. This was the first mouse model to mimic human PC1 deficiency.
A 2014 meta-analysis confirmed that common PCSK1 single nucleotide polymorphisms rs6232 and rs6234-rs6235 are associated with obesity in Caucasians. The association of rs6232 with obesity was stronger for childhood obesity than adult obesity. No association of rs6234-rs6235 with obesity was found in Asian populations. A 2015 study revisited PC1/3 variants in a wild-type background and found the N221D variant exhibited 30% lower enzymatic activity than wild-type; the linked Q665E-S690T polymorphisms did not show this difference. Two endoplasmic reticulum-retained mutants, G209R and G593R, induced ER stress markers and caused dominant-negative blockade of wild-type PC1/3 prodomain cleavage, decreasing wild-type expression and suggesting entry to a degradative proteasomal pathway.
A 2020 case report described a 14-year-old girl with type 2 diabetes, rapid weight gain, and a history of resistant diarrhoea in infancy. Her proinsulin level was >700 pmol/L (reference 3.60-22). Genetic analysis found a homozygous c.685G>T (p.V229F) mutation in PCSK1, not previously reported in this disorder. A separate 2020 study in high-fat diet fed mice found that exogenous alpha-1-antitrypsin A (AAT) treatment attenuated increases in plasma and white adipose tissue neutrophil elastase and neutrophil accumulation without affecting body weight. AAT treatment enhanced whole-body insulin sensitivity, attributed to higher insulin-dependent p-AktSer473 and reduced inflammation markers in white adipose tissue. No effects were seen in chow-fed mice.
What is still missing: no clinical trial of any drug for obesity due to prohormone convertase 1 deficiency has been reported. The AAT study was in diet-induced obese mice, not in a PC1-deficient model. No human data on AAT in this condition exist. Patient stratification by specific PCSK1 mutation type (homozygous loss-of-function versus common risk polymorphisms) is not established for any intervention. Funding for a dedicated trial in this rare disorder is 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.
Human Molecular Genetics · 2006 · 140 citations · open access
Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice
AbstractProhormone convertase 1 (PC1) mutations lead to obesity in humans. However, Pc1 knockout mice do not become obese; in fact, they are runted due to a defect in growth-hormone releasing hormone processing, leading to the speculation that PC1 subserves different functions between mouse and human. Here, we report a novel allele of mouse Pc1 (N222D) that leads to obesity, abnormal proinsulin processing and multiple endocrinological defects. Increased energy intake and a more efficient metabolism contribute to the obesity in Pc1(N222D/N222D) mice. Defective proinsulin processing leads to glucose intolerance, but neither insulin resistance nor diabetes develop despite obesity. The obesity is associated with impaired autocatalytic activation of mature PC1 and reduced hypothalamic alpha-MSH. This is the first characterization of Pc1 mutation in a model organism that mimics human PC1 deficiency.
American Journal of Epidemiology · 2014 · 68 citations · open access
The Association of Common Variants in PCSK1 With Obesity: A HuGE Review and Meta-Analysis
AbstractCongenital deficiency of the proprotein convertase subtilisine/kexin type 1 gene (PCSK1), which encodes proprotein convertase 1/3, causes a severe multihormonal disorder marked by early-onset obesity. The single nucleotide polymorphisms (SNPs) rs6232 and rs6234-rs6235 in PCSK1 have been associated with obesity. However, case-control studies carried out in populations of different ethnicities have only partly replicated this association. Moreover, these SNPs have only weakly been associated with body mass index (weight (kg)/height (m)(2)) at a genome-wide level of significance. To investigate this discrepancy, we conducted a systematic search for studies published before December 2013 and extracted relevant data. Pooled estimates were calculated for overall and subgroup analyses. This meta-analysis confirmed the association of PCSK1 SNPs with obesity and provides the first evidence that the association between PCSK1 rs6232 and obesity is stronger for childhood obesity than for adult obesity. Moreover, we identified weak associations with body mass index and significantly stronger associations with waist circumference for rs6234-rs6235. No difference was found in the association with different obesity grades, and no association of PCSK1 rs6234-rs6235 with obesity was identified in Asian populations. This systematic Human Genome Epidemiology (HuGE) review showed convincingly that the SNPs rs6232, rs6234, and rs6235 in PCSK1 are associated with obesity in Caucasians.
Revisiting PC1/3 Mutants: Dominant-Negative Effect of Endoplasmic Reticulum-Retained Mutants
AbstractProhormone convertase 1/3 (PC1/3), encoded by the gene PCSK1, is critical for peptide hormone synthesis. An increasing number of studies have shown that inactivating mutations in PCSK1 are correlated with endocrine pathologies ranging from intestinal dysfunction to morbid obesity, whereas the common nonsynonymous polymorphisms rs6232 (N221D) and rs6234-rs6235 (Q665E-S690T) are highly associated with obesity risk. In this report, we revisited the biochemical and cellular properties of PC1/3 variants in the context of a wild-type PC1/3 background instead of the S357G hypermorph background used for all previous studies. In the wild-type background the PC1/3 N221D variant exhibited 30% lower enzymatic activity in a fluorogenic assay than wild-type PC1/3; this inhibition was greater than that detected in an equivalent experiment using the PC1/3 S357G background. A PC1/3 variant with the linked carboxyl-terminal polymorphisms Q665E-S690T did not show this difference. We also analyzed the biochemical properties of 2 PC1/3 mutants, G209R and G593R, which are retained in the endoplasmic reticulum (ER), and studied their effects on wild-type PC1/3. The expression of ER-retained mutants induced ER stress markers and also resulted in dominant-negative blockade of wild-type PC1/3 prodomain cleavage and decreased expression of wild-type PC1/3, suggesting facilitation of the entry of wild-type protein to a degradative proteasomal pathway. Dominant-negative effects of PC1/3 mutations on the expression and maturation of wild-type protein, with consequential effects on PC1/3 availability, add a new element which must be considered in population and clinical studies of this gene.
Türk Pediatri Arşivi · 2020 · 6 citations · open access
A case of prohormone convertase deficiency diagnosed with type 2 diabetes
AbstractProhormone convertase 1/3, encoded by the proprotein convertase subtilisin/kexin type 1 gene, is essential for processing prohormones; therefore, its deficiency is characterized by a deficiency of variable levels in all hormone systems. Although a case of postprandial hypoglycemia has been previously reported in the literature, prohormone convertase insufficiency with type 2 diabetes mellitus has not yet been reported. Our case, a 14-year-old girl, was referred due to excess weight gain. She was diagnosed as having type 2 diabetes mellitus based on laboratory test results. Prohormone convertase deficiency was considered due to the history of resistant diarrhea during the infancy period and her rapid weight gain. Proinsulin level was measured as >700 pmol/L(3.60-22) during diagnosis. In genetic analysis, a c.685G> T(p.V229F) homozygous mutation in the PCSK1 gene was detected and this has not been reported in relation to this disorder. In conclusion, patients with recurrent resistant diarrhea during infancy followed by rapid weight gain need to be evaluated with the diagnosis of prohormone convertase deficiency.
1700-P: Exogenous a1-Antitrypsin A Enhances Insulin Sensitivity in Mice Fed a High-Fat Diet by Attenuation of Neutrophil Infiltration in Epididymal Fat
AbstractNeutrophil elastase (NE) is a serine protease expressed by neutrophils which is inhibited endogenously by α1-Antitrypsin A (AAT). Obesity is associated with increased plasma NE:AAT ratios and adipose tissue NE accumulation, which may drive obesity-associated metabolic dysfunction. Exogenous AAT is now an FDA approved treatment for AAT deficiency, therefore we investigated whether AAT treatment may also have potential therapeutic benefits for diet induced metabolic dysfunction. Standard Chow and high-fat diet (HFD) fed male C57Bl6 mice were randomized to receive 3x weekly IP injections of either AAT (2mg) or vehicle (PBS) for 10 weeks. Chow fed mice treated with recombinant AAT showed no differences in plasma NE, body weight or metabolic phenotype compared to vehicle treated control mice. However, during HFD feeding AAT treatment attenuated increases in plasma NE and white adipose tissue (WAT) NE and neutrophil accumulation without affecting circulatory neutrophil levels or body weight. Consistent with NE knockout mice being partially protected from HFD glucose intolerance, treatment of HFD fed mice with AAT enhanced whole body insulin sensitivity which was attributed to higher insulin-dependent p-AktSer473 and reduced inflammation markers in WAT but no other peripheral tissues. Treatment of 3T3L1 adipocytes with recombinant NE impaired insulin-stimulated glucose uptake andp-AktSer473, suggesting that inhibition of NE in WAT is the primary mechanism through which AAT treatment enhances insulin sensitivity. Collectively, our data suggests AAT may play a potential role in mitigating diet-induced neutrophil infiltration in WAT insulin resistance. Disclosure R.F. D’Souza: None. J.S.T. Woodhead: None. S.W. Masson: None. S.L. James: None. C. Hedges: None. T.L. Merry: None. Funding Health Research Council of New Zealand
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.
