DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for diphtheria — screening already-approved drugs against its 6-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleDiphtheria maps to a 6-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 diphtheria 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
heat shock protein 90 alpha family class A member 1 (HSP90AA1) — HSP90AA1 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 atpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7KRJ · 2.56 Å · ligand ADENOSINE-5'-TRIPHOSPHATE (ATP). Experimental structure, not a prediction.
What the evidence adds up to
The diphtheria toxin receptor was identified in 1991 as a 14.5 kDa protein purified from Vero cell membranes, which forms a complex of 60–90 kDa in the presence of detergent. By 2003, transgenic mice expressing this receptor were shown to be as sensitive to diphtheria toxin as humans, providing an animal model for testing antidotes. In 2020, researchers exploited the receptor’s internalisation pathway to create a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal enzyme TPP1; this chimeric protein bound with high affinity to target cells and showed superior uptake over TPP1 alone in the brains of TPP1-deficient mice after intracerebroventricular injection.
Spontaneous resistance to diphtheria toxin in the human cell line EUE occurs at a frequency below 8 × 10⁻⁶, but ultraviolet light can increase that frequency up to 1000-fold, with maximum recovery of resistant mutants after a short expression period followed by a decline on subsequent passages. This indicates that mutation can confer toxin resistance in human cells, though the mechanism is not described in these abstracts.
A study from the Kumaun region of India reported 61 cases of diphtheria over six years (2005–2010), with a mean age of 5.16 years and nearly all cases unimmunised for DPT despite having received oral polio vaccine. The authors call for increased awareness and acceptability of childhood immunisation. A 1940 review notes that the Schick test is a satisfactory method for determining susceptibility to diphtheria, though a negative reaction is no absolute guarantee against the disease; it cites reports of clinical diphtheria occurring in children with negative Schick tests after prophylactic treatment.
What remains missing is a modern, well-funded clinical trial of any diphtheria treatment beyond antitoxin and antibiotics. The transgenic mouse model from 2003 could be used to test new antidotes, but no such studies are reported here. The 2020 chimera work is aimed at lysosomal storage disease, not diphtheria itself. No data on patient stratification by immune status or toxin sensitivity are provided.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Molecular Microbiology · 2003 · 46 citations · open access
Transgenic mice expressing the diphtheria toxin receptor are sensitive to the toxin
AbstractWhereas diphtheria and the mechanism of action of diphtheria toxin, the bacterial molecule that induces the disease, have been studied and understood for some time, the receptor that allows animal cells to bind the toxin escaped identification until recently. The receptor was identified by its ability to confer toxin-sensitivity to mouse cells, which are normally toxin-resistant. Although mice are also naturally resistant, we now demonstrate that transgenic mice expressing the diphtheria toxin receptor are as sensitive to the toxin as are humans and other toxin-sensitive animals. These transgenic mice provide a suitable model for studying modern antidotes for diphtheria.
Journal of Biological Chemistry · 1991 · 34 citations · open access
Purification of diphtheria toxin receptor from Vero cells.
AbstractDiphtheria toxin receptor has been solubilized from Vero cell membranes with octyl beta-D-glucoside. CRM197, the product of a mutated diphtheria toxin gene, was used for the identification of the receptor. The binding activity of the solubilized receptor was assayed by precipitating the receptor with acetone in the presence of phospholipids and carrier proteins. The solubilized receptor was purified by the combination of several chromatographic steps in the presence of the detergent, resulting in about a 10(6)-fold purification of the receptor. The purified receptor showed essentially a single band of 14.5 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When partially purified receptor fractions were subjected to ligand blotting analysis using 125I-CRM197 as the probe, the 14.5-kDa protein and a few minor protein bands were identified as diphtheria toxin-binding molecules. These results show clearly that the 14.5-kDa protein is the diphtheria toxin receptor, or at least the major diphtheria toxin-binding molecule. When partially purified receptor was applied to a Sephacryl S-300 column in the presence of detergent, the receptor was eluted in the fractions corresponding to the 60-90-kDa size range. This suggests that the protein forms a complex with itself or with another protein.
Science Advances · 2020 · 16 citations · open access
Exploiting the diphtheria toxin internalization receptor enhances delivery of proteins to lysosomes for enzyme replacement therapy
AbstractEnzyme replacement therapy, in which a functional copy of an enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases. The inefficient uptake of recombinant enzymes via the mannose-6-phosphate receptor, however, prohibits the broad utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endolysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that chimeric TPP1 binds with high affinity to target cells and is efficiently delivered into lysosomes. Further, we show superior uptake of chimeric TPP1 over TPP1 alone in brain tissue following intracerebroventricular injection in mice lacking TPP1, demonstrating the potential of this strategy for enhancing lysosomal storage disease therapy.
Journal of Drug Delivery and Therapeutics · 2013 · 4 citations · open access
A STUDY OF DIPHTHERIA MENACE IN KUMAUN REGION OF UTTARAKHAND STATE IN INDIA
AbstractDiphtheria a vaccine preventable disease continues to affect children in Uttarakhand. WHO case definition for surveillance was used to identify diphtheria cases and describe their demographic characteristics. Sixty-one cases of diphtheria reported for treatment during six year period from 2005-2010. Mean age of cases was 5.16 ± 2.9 years and nearly 71% presented in acute phase of the disease. Nearly all cases were unimmunized for DPT but had received oral polio vaccine. There is an urgent need to increase awareness and acceptability of immunization program for all childhood diseases. Keywords: diphtheria, immunization, vaccine.
American Journal of Public Health and the Nations Health · 1947 · 4 citations · open access
Present Recommendations Concerning Treatment and Prophylaxis of Diphtheria
AbstractPresent Recommendations Concerning Treatment and Prophylaxis of Diphtheria Franklin H. Top CopyRight*Presented before a Joint Session of the Health Officers, Epidemiology, and Laboratory Sections of the American Public Health Association at the Seventy-fourth Annual Meeting in Cleveland, Ohio, November 11, 1946. https://doi.org/10.2105/AJPH.37.5.549 Published Online: August 29, 2011
Induction of diphtheria toxin-resistant mutants in human cells by ultraviolet light
AbstractStable spontaneous mutants resistant to the protein synthesis inhibitor diphtheria toxin (DT) have been selected in human cell line EUE at a very low frequency (less than 8 x 10(-6)). U.v.-induced mutation has been quantitatively measured: treatment of cells with u.v. light increased the frequencies of diphtheria toxin resistant (DTr) mutants up to 1000-fold. The maximum recovery of DTr mutants was observed after a short expression period, for all u.v. doses tested, and was followed by a decrease in mutation frequency on subsequent passages.
Archives of Pediatrics and Adolescent Medicine · 1940 · 1 citations
EXPERIMENTAL STUDIES ON IMMUNITY IN DIPHTHERIA
AbstractIt is now generally believed that the Schick test is a satisfactory method of determining susceptibility to diphtheria, although a negative reaction is no absolute guarantee against contraction of the disease. Top,<sup>1</sup>in a recent survey of the literature, came to the conclusion that there is no reasonable doubt that a person who reacts negatively to the Schick test will resist ordinary risks of infection. Divergencies between the Schick reaction and the content of serum antitoxin have been reported repeatedly.<sup>2</sup> Reports on the occurrence of clinical diphtheria in patients with negative reactions to Schick tests are scarce. A review may be found in an article by Underwood.<sup>3</sup>Recently, Morison and Roberts<sup>4</sup>reported on 146 cases of clinical diphtheria among 18,800 prophylactically treated children. Forty of the children affected had negative Schick reactions after the treatment, while 106 had received three injections of immunizing substance but their
THE ANTISEPTIC VERSUS THE ANTITOXIN TREATMENT OF DIPHTHERIA.
AbstractI am much interested in the subject of diphtheria and its treatment, and from what I have been able to observe, it would seem that the point at issue at the present time is this, viz., is or is not antitoxin the best treatment yet offered for the cure of diphtheria? I have had very limited experience with the remedy, but as yet can not feel that it is worthy of the advertising it has received at the hands of the profession. This conclusion has not entirely been arrived at from the few cases in which I have used the remedy, but from all the information I have been able to obtain from reading the arguments<i>pro</i>and<i>contra</i>, in medical literature. Let us consider a few published facts. Producers of antitoxin are urging the profession to use the serum in the very early stages of the disease and in
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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