Summary

This deposit publishes 1,908,879 distinct sequence-and-form-variant compositions targeting the MT1 (gene MTNR1A, UniProt P48039) and MT2 (gene MTNR1B, UniProt P49286) melatonin receptors as allosteric peptide modulators. The compositions decompose to 35,198 unique linear backbone sequences and 90 distinct chemistry form-variants spanning seven chemistry families: lipidation, PEGylation, glycosylation, Fc fusion, prodrug variants, glucuronidation, and macrocyclization, plus salt forms and single-residue swap variants. Every disclosed composition is novel against an 11-zone real-patent-grounded markush exclusion corpus surveyed on 2026-05-02 and is dedicated to the public domain as prior art under 35 U.S.C. §102 and analogous foreign-jurisdiction novelty provisions: EPC Article 54, UK Patents Act §6, Japanese Patent Act §29, and Chinese Patent Law Article 22. The deposit prevents any party from later claiming composition-of-matter novelty on any of the disclosed (backbone × form-variant × cyclization) tuples in applications filed after the deposit date.

The disclosure architecture is three-tier: 100 Tier 1 candidates ship with a 15-section per-candidate dossier, 1,000 Tier 2 candidates ship as table-form per-candidate stubs, and the remaining 1,907,779 candidates are documented in the JSON-Lines manifest plus a WIPO Standard ST.26 Sequence Listing at the unique-backbone level for examiner-side BLAST searchability. The deposit's universal-protocol package, comprising eight family-level synthesis protocols and three form-variant-independent characterization protocols, provides the §102 enablement carrier that propagates from the bundle level to every individual disclosed composition.

Readiness tier breakdown

A readiness-quality letter (A / B / C / D) summarizes each candidate's predicted-affinity tier. The letter is a pure-pharmacology readout. The deposit makes no clinical or therapeutic-efficacy claim.

Pharmacology framing

The candidate compositions are designed against the MT1/MT2 allosteric site as a hypothesis-driven scaffold. The design hypothesis is informed by an 18-residue endozepine-derived hypothesis scaffold sequence (QATVGDVNTDRPGLLDLK) tagged in the Coracle Research scaffold registry as a research-grade MT1/MT2 allosteric reference at approximately 100 nM apparent Kd. The scaffold is not a contiguous fragment of human Diazepam Binding Inhibitor (UniProt P07108): the closest 18-residue DBI window (residues 35-52, QATVGDINTERPGMLDFT) shares 13 of 18 positions with the scaffold and differs at positions 7, 10, 14, 17, and 18. The deposit treats the scaffold as a hypothesis sequence rather than a literature-published peptide. The classical published pharmacology of the endozepine peptide family (full-length DBI, octadecaneuropeptide ODN, triakontatetraneuropeptide TTN) describes activity at the GABA-A receptor benzodiazepine binding site and at the translocator protein TSPO; the MT1/MT2 allosteric assignment is research-grade and is not the dominant published interpretation. The §102 prior-art certification of the disclosed compositions is not contingent on the anchor's specific receptor activity. Bench validation per the deposit's universal binding-affinity assay (radioligand displacement at MT1 and MT2 with [125I]-2-iodomelatonin) and universal functional-readout assay (cAMP HTRF with allosteric-cooperativity discrimination) is the authoritative reference for any specific candidate's MT1/MT2 binding profile.

Form-variant chemistry families

The deposit's form-variant axis spans seven chemistry families:

Universal-protocol package

The deposit provides eleven universal protocols organized into two layers. Form-variant-family-dependent synthesis protocols (eight files) cover all chemistry families. Form-variant-independent characterization protocols (three files) cover the binding-affinity assay, the functional readout, and the QC standard.

Family-level synthesis protocols

• Base Fmoc solid-phase peptide synthesis (unmodified linear and salt-form variants)
• Lipidation (988,540 candidates: C8-C20 fatty-acid attachment via amide chemistry, with γGlu spacer for di-acid variants)
• PEGylation (397,104 candidates: NHS-ester PEG attachment at N- or C-terminus, PEG2 through PEG40-branched)
• Glycosylation (303,985 candidates: pre-glycosylated Fmoc building blocks for O-glycans, chemoenzymatic for N-Man5)
• Fc fusion (105,606 candidates: mammalian CHO/HEK293 expression of IgG1-fusion construct, wild-type or LALA-silent)
• Prodrug (78,314 candidates: ester-masked or glycopeg conjugate)
• Glucuronidation (35,202 candidates: chemoenzymatic glucuronide-linker installation)
• Cyclization (36 candidates: head-to-tail amide, side-chain lactam, hydrocarbon staple via RCM, oxime, triazole via CuAAC, lactone)

Form-variant-independent universal protocols

• MT1 / MT2 radioligand-displacement binding-affinity assay using [125I]-2-iodomelatonin tracer (PerkinElmer NEX236) with Cheng-Prusoff IC₅₀→Kd correction. Anchor reference Witt-Enderby and Dubocovich, Mol Pharmacol 1996.
• cAMP HTRF functional readout (Cisbio HTRF cAMP Gi Dynamic Kit) at MT1 and MT2 stable HEK293 cell lines, with allosteric-cooperativity discrimination per the Christopoulos-Kenakin allosteric ternary complex model.
• RP-HPLC + ESI-MS + AAA quality control standards.

Each universal protocol is universally applicable to every disclosed candidate within its scope without per-candidate inventive choice. This satisfies the §102 enablement element under the In re Wands factors.

WIPO ST.26 Sequence Listing

The deposit includes a WIPO Standard ST.26 Sequence Listing at the unique-backbone level (35,198 entries) with feature annotations for form-variant modifications. WIPO ST.26 has been mandatory in PCT applications since 2022-07-01; patent examiners run BLAST-style searches against the Sequence Listing corpus during every patent prosecution involving sequences. The deposit's ST.26 file ensures examiner-side findability for any later patent application claiming sequences within the disclosed space.

Stated utilities

Each disclosed composition is offered for use in the following applications, applicable as a class-level statement to every member of the disclosed set:

• Allosteric modulation of melatonin receptor MT1 and MT2 (positive, negative, neutral, and biased allosteric modulation)
• Modulation of circadian rhythm (phase-shifting, entrainment of suprachiasmatic-nucleus master clock)
• Modulation of sleep-wake cycle (sleep-onset latency, sleep maintenance, REM cycle)
• Modulation of mood and affective state where MT1 and MT2 receptor signaling has been implicated
• Modulation of pain pathways where MT1 and MT2 receptor signaling has been implicated
• Modulation of immune signaling (per published MT-receptor immunomodulatory roles)
• Modulation of cellular proliferation and oncology research (per published anti-proliferative effects of MT-receptor activation)
• Modulation of metabolic pathways (insulin secretion modulation by pancreatic-β-cell MT2 activity)
• Modulation of cardiovascular function
• Modulation of reproductive function
• Neuroprotection
• Use as research tool, screening reagent, and characterization standard in MT1/MT2 receptor pharmacology

The breadth of stated utilities is intentional: it covers every published functional role of MT1 and MT2 receptor signaling, maximizing method-of-use foreclosure surface for any specific composition-of-matter that anyone would otherwise attempt to claim post-publication.

Disclosed properties of the predicted-Kd output

The predicted Kd values in this deposit are produced by a Coracle Research predictor whose internals are not part of this disclosure. The predictor's outputs across the 1,908,879 disclosed compositions exhibit several properties that the deposit discloses explicitly so that any POSITA can interpret the numerical predictions accurately and design bench-validation work accordingly.

• Single-anchor calibration. All predicted Kd values are calibrated against the 18-residue endozepine-derived hypothesis scaffold sequence at approximately 100 nM apparent Kd. The deposit does not provide a held-out experimental validation set; per-candidate fold-error against bench measurement is not statable from a single anchor. Predicted Kd should be read as a research-grade design-prioritization signal.
• Quantization in predicted Kd. Across the 1,908,879 rows in summary.csv, the predicted-Kd column takes 387 distinct values; the fifteen most-frequent values cover approximately 16% of all rows. Predicted Kd is a discretized output rather than a continuous regression.
• Within-backbone form-variant signal. For the typical disclosed backbone the predictor produces two distinct Kd values across the form-variant axis, one for the lipidated form-variants and one for the non-lipid form-variants (PEGylation, glycosylation, Fc fusion, prodrug, glucuronidation, cyclic). The form-variant signal is essentially binary "lipidated yes / no" rather than a quantitative chemistry-specific correction. The native scaffold is an exception, with multiple distinct Kd values across its form-variants including a 100 nM cluster matching the literature anchor reference. Bench validation is required for absolute Kd quantitation on any specific composition.
• Tier 1 design-space structure. All 100 Tier 1 candidates are at edit-distance 3 from the scaffold. The lipidated form-variants of the leading backbone are predicted at 0.0755 nM, an approximately 1300× affinity gain over the 100 nM scaffold reference predicted by a single-anchor-calibrated computational model from three substitutions. This is a research-grade design hypothesis subject to bench falsification, not an experimentally established value.
• POSITA verification path. Each disclosed composition can be independently bench-validated using the deposit's universal MT1/MT2 radioligand-displacement binding-affinity assay and the universal cAMP HTRF functional-readout assay. The bench-measured Kd and functional readout are the authoritative references for any specific composition's allosteric activity at MT1 and MT2.

The §102 prior-art certification is over the disclosed (backbone × form-variant × cyclization) compositions and does not rest on the predictor's specific predicted-Kd values being correct. A bench-measured Kd that diverges from the predicted Kd does not weaken the §102 prior-art posture for that composition; it informs the predictor's accuracy on that specific chemistry.

What this disclosure does not claim

The deposit asserts §102 anticipation only. Method-of-use claims for indications outside the eleven stated utilities, formulation claims, combination-therapy claims, and compositions including a disclosed peptide as a non-disclosed component are unaffected. The deposit does not claim any in-vivo activity, clinical safety, or therapeutic efficacy. Predicted pharmacology and projected costs are computational and reference-anchored estimates calibrated to literature; bench validation and clinical trials are required before any therapeutic assertion. The deposit does not include or expose Coracle Research's underlying computational methodology.

How to access the deposit

The full deposit is available at Zenodo: DOI 10.5281/zenodo.20012096. The bundle includes the cover PDF, the deposit README with the §102 declaration verbatim, the master sortable index with Methods block, eleven shortlists (Tier 1, Tier 2, patent-adjacent, per-form-variant-family), the summary CSV, the all-candidates FASTA, the per-candidate JSON-Lines manifest for all 1,908,879 compositions, the WIPO ST.26 Sequence Listing at unique-backbone level, the universal-protocol package (eleven files), and the OpenTimestamps Bitcoin block-header attestation of the bundle SHA-256 hash for cryptographic date proof.

Citation

Coracle Research. Drop 07: Class-Wide §102 Disclosure of MT1 / MT2 Melatonin-Receptor Allosteric Peptide Modulators. 1,908,879 sequence-distinct candidates across 35,198 unique backbones and 90 form-variant chemistries. Zenodo, 2026. DOI: 10.5281/zenodo.20012096.

Inquiries

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