DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for adenylosuccinate lyase deficiency — 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 moduleAdenylosuccinate lyase deficiency 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 adenylosuccinate lyase 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
adenylosuccinate lyase (ADSL) — ADSL 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 4FLC · 2.6 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Adenylosuccinate lyase deficiency is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. A 2021 survey of 18 patients (12 males, median age 10.9 years) from 13 families found age at onset from birth to three years (median 0.63 years) and age at diagnosis from two months to 17 years (median 6.4 years). The first sign was psychomotor delay in 8 of 18 patients, epilepsy in 3, both in 3, and apneas, hypotonia, or nystagmus in single cases. One patient had a fatal neonatal form, seven fit type I, nine had a milder type II, and two showed a very mild phenotype. Eighteen different variants were found, six not previously reported; all but two were missense. Only about 40 published cases existed as of 2007, and the condition presents in early life with mental retardation and seizures.
A 2003 study using Bacillus subtilis as a model constructed mutations corresponding to severe human deficiencies (Met10Leu, Ile123Trp, Thr367Arg). The altered enzymes retained substantial catalytic activity with small changes in kinetic parameters, but all showed marked thermal instability. I123W caused protein aggregation and changes in circular dichroism spectra; T367R altered quaternary structure. Instability was lessened by subunit complementation with wild-type enzyme under mild conditions. A 2010 study in E. coli identified a point mutation (E115K) in purB (encoding adenylosuccinate lyase) that slowed growth in minimal media; reversing the mutation restored normal growth.
A 2011 paper described a rhodamine-based boronic acid that linearly responds to increasing AICAr concentrations in human urine, offering a detection method for ADSL deficiency since AICAr is a model riboside for the substrates S-Ado and SAICAr. No clinical trial data exist for any drug treatment in these patients. What is still missing is any funded clinical trial, a clear patient stratification strategy beyond the type I/II distinction, and any evidence that correcting the enzyme defect in humans alters the neurological course.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Protein Science · 2003 · 20 citations · open access
The characterization of mutant <i>Bacillus subtilis</i> adenylosuccinate lyases corresponding to severe human adenylosuccinate lyase deficiencies
AbstractAdenylosuccinate lyase is a homotetramer that catalyzes two discrete reactions in the de novo synthesis of purines: the cleavage of adenylosuccinate and succinylaminoimidazole carboxamide ribotide (SAICAR). Several point mutations in the gene encoding the enzyme have been implicated in human disease. Bacillus subtilis adenylosuccinate lyase was used as a model system in which mutations were constructed corresponding to those mutations associated with severe human adenylosuccinate lyase deficiency. Site-directed mutagenesis was utilized to construct amino acid substitutions in B. subtilis adenylosuccinate lyase; Met(10), Ile(123), and Thr(367) were replaced by Leu, Trp, and Arg, respectively, and the altered enzymes were expressed in Escherichia coli. These purified enzymes containing amino acid substitutions were found to have substantial catalytic activity and exhibit relatively small changes in their kinetic parameters. The major deviations from the wild-type-like behavior were observed upon biophysical characterization. All of these enzymes with amino acid replacements are associated with marked thermal instability. I123W adenylosuccinate lyase exhibits notable changes in the circular dichroism spectra, and a native gel electrophoresis pattern indicative of some protein aggregation. T367R also exhibits alterations at the quarternary level, as reflected in native gel electrophoresis. Experimental results, combined with homology modeling, suggest that the altered enzymes are primarily structurally impaired. The enzyme instability was found to be lessened by subunit complementation with the wild-type enzyme, under mild conditions; these studies may have implications for the in vivo behavior of adenylosuccinate lyase in heterozygous patients. Residues Met(10), Ile(123), and Thr(367) appear to be located in regions of the enzyme important for maintaining the structural integrity required for a stable, functional enzyme.
Applied and Environmental Microbiology · 2010 · 19 citations · open access
Restoration of Growth Phenotypes of <i>Escherichia coli</i> DH5α in Minimal Media through Reversal of a Point Mutation in <i>purB</i>
AbstractA point mutation (E115K) resulting in slower growth of Escherichia coli DH5alpha and XL1-Blue in minimal media was identified in the purB gene, coding for adenylosuccinate lyase (ASL), through complementation with an E. coli K-12 genomic library and serial subcultures. Chromosomal modification reversing the mutation to the wild type restored growth phenotypes in minimal media.
Inhibition of defective adenylosuccinate lyase by HNE: A neurological disease that may be affected by oxidative stress
AbstractAdenylosuccinate lyase is an enzyme of fumarase superfamily that participates in the purine biosynthetic pathway, catalysing the nonhydrolytic cleavage of succinyl groups from SAICA ribotide and adenylosuccinate. Enzyme defects are associated with a human inherited disease, which arises from single point mutations to the gene and results in mild to severe psychomotor retardation, epilepsy, muscle wasting, and autistic features. Adenylosuccinate lyase activity is lost to a different extent in the patients. Diminished levels of enzyme have been attributed to loss of catalytic activity, protein instability, or environmental factors. P100A/D422Y mutation represents a feasible model for studying the effect of cell milieu on the activity of the impaired enzyme. The defective enzyme is inhibited by micromolar concentrations of trans-4-hydroxy-2-nonenal (HNE), a major product of membrane peroxidation that has been found to accumulate in brain tissues of patients with neurodegenerative disorders. It is suggested that inactivation of defective adenylosuccinate lyase by HNE and other membrane peroxidation products may account, at least in part, for the impairment of neurological functions and recurrent worsening of the symptoms.
Australian Journal of Chemistry · 2011 · 2 citations
Progress Towards Simple and Direct Detection of Adenylosuccinate Lyase Deficiency in Human Urine
AbstractA rhodamine based boronic acid linearly responds to increasing 5-aminoimidazole-4-carboxamide riboside (AICAr) concentrations in human urine. This method is thus an advance in detecting adenylosuccinate lyase (ADSL) deficiency as AICAr is a model riboside for the ADSL substrates succinyladenosine (S-Ado) and succinylaminoimidazolecarboxamide riboside (SAICAr). ADSL deficiency is a rare but devastating disease of de novo purine synthesis in infants. Its diagnosis is also significant as it is one of the autism spectrum disorders.
AbstractA disorder of purine synthesis, adenylosuccinate lyase deficiency is a rare condition, with only about 40 published cases. It presents in early life with mental retardation and seizures. Although no specific diagnostic criteria have been proposed for the clinical syndrome, Table 1 summarizes clinical findings in 20 patients and may be useful as a guide in suspecting the diagnosis.
Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency
AbstractAbstract Background Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype–phenotype correlations. Results Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense. Conclusions The study adds more details on the spectrum of ADSLD patients’ phenotypes and molecular data.
Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency
AbstractAbstract Background Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype–phenotype correlations. Results Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense. Conclusions The study adds more details on the spectrum of ADSLD patients’ phenotypes and molecular data.
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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