ALEMBIC LABS
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distillation №68

FOXO4-DRI — Fragment/truncation: retain only the FOXO4 CR3-mimetic N-terminal helix (residues 1-23, LTLRKEPASEIAQSILEAYSQNG) and remove the entire C-terminal cationic CPP tail (residues 24-46) plus the GG linker, yielding a clean 23-residue helix-only peptide for evaluating the intrinsic p53-binding interface.

FRAGMENT/TRUNCATION: RETAIN ONLY THE FOXO4 CR3-MIMETIC N-TERMINAL HELIX (RESIDUES 1-23, LTLRKEPASEIAQSILEAYSQNG) AND REMOVE THE ENTIRE C-TERMINAL CATIONIC CPP TAIL (RESIDUES 24-46) PLUS THE GG LINKER, YIELDING A CLEAN 23-RESIDUE HELIX-ONLY PEPTIDE FOR EVALUATING THE INTRINSIC P53-BINDING INTERFACE.LONGEVITYMay 4, 2026[ DISCARDED ]
[↓ download report.pdf]
average confidence
60.8%
pTM
0.39452722668647766
ipTM
0.20455197989940643
binding Δ
—
agreement
—
target
Cellular tumor antigen p53
uniprot
P04637
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3D structure

// booting Mol* viewer

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chain A — peptide (plasma red)chain B+ — target / context (white)
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AI analysis

tldr

—

detailed analysis

—

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research data

A

known activity

// not yet provided by clinical agent

B

biohacker use

// not yet provided by clinical agent

C

mechanism class

// not yet provided by clinical agent

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folding metrics

// no per-residue pLDDT trace — Boltz-2 returned summary metrics only

aggregation propensity (window)

17 windows

confidence metrics

pLDDT mean
0.61
pTM
0.39
ipTM
0.20
Boltz ↔ Chai
—
cross-validated (borderline pLDDT)
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domain annotations

// not yet annotated by clinical / structural agents

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structural caption

The 23-residue FOXO4 CR3-mimetic fragment was co-folded with p53 TAD2 (residues 35-59) by Boltz-2, yielding moderate intra-chain confidence (pLDDT 0.61) but very low interface confidence (ipTM 0.20, pTM 0.39). The peptide is plausibly modeled as a short helical segment, but the docking pose against the p53 TAD2 acidic interface is not supported by the ensemble. No affinity-module output was produced, and no Chai-1 model was available for cross-validation. The structure therefore does not provide an interpretable readout of the FOXO4-p53 interface.

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peptide profile

These are sequence-based heuristic estimates, not wet-lab measurements. Real aggregation propensity requires TANGO/Aggrescan, real BBB permeability requires QSAR models, and real half-life requires PK studies. Treat the numbers as ranked indicators — useful for comparing variants, not for absolute claims.

aggregation propensity
heuristic
0.116
● good
Predicted likelihood of self-aggregation. Lower is better.
≤ 0.40 good · ≤ 0.80 moderate
source: Kyte-Doolittle window proxy
stability prediction
heuristic
0.61
● moderate
Composite stability score. Higher = more stable in solution.
≥ 0.70 good · ≥ 0.40 moderate
source: charge / proline / length composite
BBB penetration
heuristic
0.085
● —
Estimated blood-brain barrier permeability. Goal depends on target tissue.
≥ 0.50 high · ≥ 0.20 moderate
source: hydrophobic fraction proxy
half-life estimate
heuristic
moderate-to-long (~1–6 hours)
● —
In-silico estimated plasma half-life range.
text estimate
source: length-bucket heuristic
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known binders

// no ChEMBL binders found for this target

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agent findings

3 findingslast updated: 2026-05-04 16:32:23 UTC
researcher: 1literature: 1structural: 1
☿RESEARCHER agentclaude-opus-4-7
2026-05-04 15:59:07 UTC· 19.1s● COMPLETED
Fragment/truncation: retain only the FOXO4 CR3-mimetic N-terminal helix (residues 1-23, LTLRKEPASEIAQSILEAYSQNG) and remove the entire C-terminal cationic CPP tail (residues 24-46) plus the GG linker, yielding a clean 23-residue helix-only peptide for evaluating the intrinsic p53-binding interface.
🜍LITERATURE agentclaude-sonnet-4-6
2026-05-04 15:59:26 UTC· 55.9s● COMPLETED
8 PubMed + 1 preprints synthesised
🜔STRUCTURAL agentclaude-opus-4-7
2026-05-04 16:00:22 UTC· 32m 0s● COMPLETED
Truncation to the helix-only fragment did not raise pLDDT above the >0.70 target predicted by the hypothesis (0.61 vs. prior 0.56-0.61 for full-length), and the interface metric (ipTM 0.20) is poor. The hypothesis that the CPP tail was the primary source of conformational noise is not supported by this single run — confidence remained in the same regime. Combined with literature (Bourgeois et al. 2025) reporting that the CPP tail itself contributes to p53 TAD2 binding, the weak interface here is
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caveats

  • ─in silico prediction only — requires wet lab validation
  • ─single-run prediction (not ensembled)
  • ─predicted properties may not reflect biological reality
  • ─this is research, not medical advice
  • ─modified peptides have not been synthesized or tested
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data

[↓ download fold.json][↓ download structure.pdb][⊘ on-chain unavailable][⎘ copy permalink]
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works cited

  1. [1]

    (2025). The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI

    · PubMed PMID ↗

  2. [2]

    (2022). Identification of Hotspots in Synthetic Peptide Inhibitors of the FOXO4:p53 Interaction

    · PubMed PMID ↗

  3. [3]

    (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice

    · PubMed PMID ↗

  4. [4]

    (2024). FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells

    · PubMed PMID ↗

  5. [5]

    (2025). FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation

    · PubMed PMID ↗

  6. [6]

    (2025). FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway

    · PubMed PMID ↗

  7. [7]

    (2021). Targeting senescence-like fibroblasts radiosensitizes non-small cell lung cancer and reduces radiation-induced pulmonary fibrosis

    · PubMed PMID ↗

  8. [8]

    (2023). Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progress

    · PubMed PMID ↗