DeCure for Glycosylphosphatidylinositol biosynthesis defect 16
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for glycosylphosphatidylinositol biosynthesis defect 16 — 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 moduleGlycosylphosphatidylinositol biosynthesis defect 16 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 glycosylphosphatidylinositol biosynthesis defect 16 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
The 1993 cloning of PIG-A established that this gene encodes a protein required for the synthesis of N-acetylglucosaminyl-phosphatidylinositol, the earliest intermediate in GPI-anchor biosynthesis. By 2014, next-generation sequencing had enabled the discovery of many new genetic disorders in glycosylation pathways, including those affecting GPI anchors, and had broadened the recognised clinical phenotypes. The specific gene defects and their biochemical properties are now being identified and validated using structural biochemistry and its more refined descendants.
A 2002 study tested 22 synthetic analogues of the GPI intermediate GlcNα1-6-myo-inositol-1-HPO₄-sn-1,2-dipalmitoylglycerol in cell-free systems from Trypanosoma brucei and human HeLa cells. One compound, 4-deoxy-d-GlcNα1-6-d-myo-inositol-1-HPO₄-sn-1,2-dipalmitoylglycerol, inhibited both the trypanosomal and human pathways. Two other analogues, 4-O-methyl-d-GlcNα1-6-d-myo-inositol-1-HPO₄-sn-1,2-dipalmitoylglycerol and the 4′-epimer d-GalNα1-6-d-myo-inositol-1-HPO₄-sn-1,2-dipalmitoylglycerol, were neither substrates nor inhibitors. The 6-OH of the α-d-GlcN residue was not required for substrate recognition in either system, but the 3-OH group was essential in both. Parasite-specific recognition of the β-linked analogue d-GlcNβ1-6-d-myo-inositol-1-HPO₄-sn-1,2-dipalmitoylglycerol was striking.
The trypanosomal α-mannosyltransferases, inositol acyltransferase and ethanolamine phosphate transferase did not recognise the 2-, 3-, 4- or 5-OH groups of the d-myo-inositol residue, whereas the human inositol acyltransferase and/or first α-mannosyltransferase recognised one or more of these groups. All lipid analogues tested served as substrates in both systems, indicating that a precise lipid structure and stereochemistry are not essential for substrate recognition. However, an analogue with a single C18:0 alkyl chain in place of sn-1,2-dipalmitoylglycerol was a better substrate in the trypanosomal system than in the HeLa system. These findings were directed at designing specific inhibitors of the trypanosomal GPI pathway, not at treating human GPI biosynthesis defects.
No abstract describes any drug tested in patients with glycosylphosphatidylinositol biosynthesis defect 16, nor any clinical trial, survival data, or response rates for that condition. What is missing is any clinical research funding, any trial design for this specific disorder, and any patient stratification that might connect the biochemical findings from 2002 to a human disease.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 1993 · 537 citations
The Cloning of PIG-A, a Component in the Early Step of GPI-Anchor Biosynthesis
AbstractThe glycosylphosphatidylinositol (GPI) anchor is a membrane attachment structure of many proteins and occurs in a wide variety of eukaryotes from yeasts to mammals. The structure of the core of the GPI anchor is conserved in protozoa and mammals and so is its biosynthetic pathway. A complementary DNA encoding a human protein termed PIG-A (phosphatidylinositol glycan-class A) was cloned. PIG-A was necessary for synthesis of N-acetylglucosaminyl-phosphatidylinositol, the very early intermediate in GPI-anchor biosynthesis.
Journal of Inherited Metabolic Disease · 2014 · 60 citations
Human genetic disorders involving glycosylphosphatidylinositol (GPI) anchors and glycosphingolipids (GSL)
AbstractGlycosylation - enabling genes are thought to comprise approximately 1-2 % of the human genome, thus, it is not surprising that more than 100 genetic disorders have been identified in this complex multi-pathway cellular process. Recent advances in next generation sequencing technology (NGS) have led to the discovery of genetic causes of many new disorders and importantly highlighted the broad phenotypes that occur. Here we will focus on two glycosylation pathways that involve lipids; glycosylphosphatidylinositol (GPI) anchors and glycosphingolipids (GSL) with emphasis on the specific gene defects, their biochemical properties, and their expanding clinical spectra. These disorders involve the intersection of two pathways: lipids and carbohydrates. Studies of both pathways were founded on structural biochemistry. Those methods and their more refined and sensitive descendants can both identify the specific genes that cause the disorders and validate the importance of the specific mutations.
Journal of Biological Chemistry · 2002 · 20 citations · open access
Specificities of Enzymes of Glycosylphosphatidylinositol Biosynthesis in Trypanosoma brucei and HeLa Cells
AbstractA series of synthetic analogues of d-GlcN alpha 1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol, consisting of 22 variants of the d-GlcN or lipid components, were tested in trypanosomal and human (HeLa) cell-free systems. The assays measured the abilities of the analogues to act as substrates or inhibitors of the enzymes of glycosylphosphatidylinositol biosynthesis downstream of GlcNAc-phosphatidylinositol (GlcNAc-PI) de-N-acetylase. One compound, 4-deoxy-d-GlcN alpha 1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol, proved to be an inhibitor of both the trypanosomal and HeLa pathways, whereas 4-O-methyl-d-GlcN alpha 1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol and the 4'-epimer, d-GalN-alpha1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol, were neither substrates nor inhibitors. The results with other analogues showed that the 6-OH of the alpha-d-GlcN residue is not required for substrate recognition in the trypanosomal and human pathways, whereas the 3-OH group is essential for both. Parasite-specific recognition of the beta-linked analogue d-GlcN beta 1-6-d-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol is striking. This suggests that, like the GlcNAc-PI de-N-acetylase, the trypanosomal glycosylphosphatidylinositol alpha-mannosyltransferases, inositol acyltransferse and ethanolamine phosphate transferase, do not recognize the 2-, 3-, 4-, and 5-OH groups of the d-myo-inositol residue, whereas the human inositol acyltransferase and/or first alpha-mannosyltransferase recognizes one or more of these groups. All of the various lipid analogues tested served as substrates in both the trypanosomal and HeLa cell-free systems, suggesting that a precise lipid structure and stereochemistry are not essential for substrate recognition. However, an analogue containing a single C18:0 alkyl chain in place of sn-1,2-dipalmitoylglycerol proved to be a better substrate in the trypanosomal than in the HeLa cell-free system. These findings should have a bearing on the design of future generations of specific inhibitors of the trypanosomal glycosylphosphatidylinositol biosynthetic pathway.
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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