STRC Research

H01 · Pharmacochaperone E1659A

16 min read

h01 — Pharmacochaperone E1659A

mech. Small-molecule fold-stabilizer binds K1141 pocket on E1659A STRC, rescuing misfolded stereocilin. delivery. Oral/topical small molecule; round-window permeability precedent exists. patient-fit. Maternal allele c.4976A>C E1659A directly targeted; extracellular concern flags mechanism.

status

A-tier. Reframed from “NORMAL monotherapy” → “MILD-MODERATE adjunct lever with conditional NORMAL” per Misha Compound-Het Therapy Stack Model. K1141 pocket site-druggable (Phase 5c GREEN), chemistry-limited on current shortlist (Phase 5b RED); fenamic parents not developable for pediatric target per STRC h01 Fenamic Scaffold Tox Audit 2026-04-23, tafamidis-style bioisosteric optimization is the forward path.

active compute

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(no active runs)

next-step tree

After v3b delivery:

  1. GREEN non-covalent → Phase 4h MD-scored validation on top-5 + wet-lab triage STRC h01 Phase 8 Wet-Lab Triage SOP on tafamidis-style optimized analog (parents are MD probes only per tox audit)
  2. GREEN covalent → Phase 6c selectivity audit vs proteome-wide Lys pockets + cochlear ion-channel panel (TRPM4 / Cx50 / BK / KCNQ4 / TMEM16A)
  3. YELLOW → Phase 3c v4 fragment-growing on best cluster OR Phase 6d different warhead class
  4. RED → Phase 3c v5 de novo RFdiffusion pocket design

After Phase 5d + 5e delivery:

  • Mutant K1141 stable (ΔΔG < 0.3 kcal/mol, Kd ratio < 2×) → WT-based docking validated, continue medchem on v3b hits
  • Mutant pocket shifts → Phase 3c v6: re-screen on mutant ensemble, or pivot to h11 dimer-interface rescue
  • Mutant reveals new cryptic pocket → Phase 3c v7 new-pocket screen

Recent activity

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  • h01 log
  • strc
  • h01
  • H01 WETLAB_HANDOFF_PACKET_READY_FOR_RFQ. Filed a private assay-scoping packet that reframes H01 as target-engagement feasibility, not lead-candidate nomination. Package includes a compound sheet (1-indanyl_acylsulfonamide_SO2Me_-Cl affinity track, adamantyl_acylsulfonamide_SO2Me_-Cl practical/ADMET backup, optional adamantyl_-CF3 residence comparator), a gap matrix, and an RFQ email template. P0 empirical gaps are physical compounds, recombinant STRC K1141-fragment reagent, and direct binding/stabilization data. Ranking delta: A held; mech 4 / deliv 3 / misha_fit 4 unchanged. Next step changes to send separate RFQs for custom synthesis, STRC 1066-1216 WT/E1659A fragment expression, and DSF/nanoDSF + SPR/BLI/MST assay-scoping; production holo MD/MM-PBSA is paper-grade support, not a wetlab-contact blocker. → STRC h01 Wetlab Handoff Packet 2026-04-27
  • Phase 9b MINRELAX_MULTIFRAME_SMOKE_SUPPORTIVE. Reused the repaired matched WT/E1659A Amber dry complexes for v5.3__aq3__adamantyl__acylsulfonamide_SO2Me__-Cl, ran 60 extra implicit-GB minimization steps with protein :1-1775 restrained at 10 kcal/mol/A^2 and ligand free, wrote 6 frames per condition, and rescored with MMPBSA.py GB (igb=5, saltcon=0.150). WT DELTA TOTAL -15.84 +/- 0.46 SEM kcal/mol; E1659A -18.18 +/- 0.09; E1659A-minus-WT -2.35 kcal/mol. Ranking delta: A held; mech 4 / deliv 3 / misha_fit 4 unchanged. P0 next: production explicit-solvent holo MD / MM-PBSA if Phase 9b is to become paper-grade, otherwise keep this as a caveated robustness smoke. → STRC h01 Phase 9b Min-Relax Multi-Frame MM-GBSA Smoke 2026-04-27

evidence

  • STRC Pharmacochaperone Virtual Screen E1659A — main hypothesis; Phases 0-3
  • STRC Pharmacochaperone K1141 Fragment Pocket — pocket characterization
  • STRC Pharmacochaperone Phase 4 Plan — 7-gate validation ladder
  • STRC h01 Phase 4h Tafamidis Playbook Library 2026-04-23 — 30-compound bioisostere seed
  • STRC h01 Phase 8 Wet-Lab Triage SOP — 3-gate wet-lab protocol
  • STRC h01 Fenamic Scaffold Tox Audit 2026-04-23 — scaffold developability
  • STRC h01 Phase 5 MD Ensemble Rescoring 2026-04-23 — Phase 5a/5b
  • STRC h01 Phase 5c Cryptic Pocket Analysis 2026-04-23 — site stability
  • STRC h01 Phase 3c v2 Expanded Screen 2026-04-23 — expanded dock
  • STRC h01 Phase 5j APBS WT vs Mutant Pocket Electrostatics 2026-04-24 — pocket-average APBS
  • STRC h01 Phase 4i APBS Pose-Transplant Rescore 2026-04-24 — per-pose APBS (Tier 4)
  • STRC h01 Phase 5k Ensemble APBS on Phase 5d Mutant MD 2026-04-24 — ensemble APBS (Tier 0)
  • STRC h01 Phase 8 v5 Library Coulomb-Aware Design 2026-04-24 — v5 library design + combined ranking
  • STRC h01 Phase 8c v5 ADMET-AI Triage 2026-04-24 — 12/20 v5 ADMET-clean vs 0/10 v3b; first clean candidate
  • STRC h01 Phase 5k-WT Matched Ensemble APBS 2026-04-25 — matched WT vs MUT ensemble; −2.79 kcal/mol, p=6.9e-12, mech 4
  • STRC h01 Phase 8d 8e 8f v5.2 Library Design 2026-04-25 — 384 ligand library; 14-compound ADMET-clean shortlist; adamantyl__CONHOH__-Cl confirmed #1
  • STRC h01 Phase 8g v5.2 Off-Target Panel 2026-04-25 — Vina off-target panel fails for all 6 ligands incl. v3b ref; Vina limitation; wet-lab required
  • Phase 7I follow-on triple (2026-04-26 01:5x) — pose ensemble, ADMET re-check, APBS off-target on Tier-1. K1141 NZ engagement carries through CONHOH→CONHOMe/phosphonate (2 Tier-1 in salt-bridge zone, tighter than ref); 5/5 ADMET-clean; CONHOH lead fails +2 kT/e off-target selectivity gate (TRPM4 +9.36 vs STRC +2.51); CONHOMe-Cl head swap reduces TRPM4 anti-selectivity by −3.24 kT/e but still fails strict gate. → artifacts/phase7i_v52_combined/{tier1_pose_stability.md, tier1_admet_recheck.md, apbs_offtarget_summary.md}
  • h01 Phase 7I v52 Combined Boltz-2 Analysis 2026-04-26 — closes v52_top3 + reframes v5.3: 12 paired ligands, head-group is the discriminator; lead adamantyl_CONHOH_-Cl Δ=−0.017 ⚪ tie on Boltz-2; CONHOMe head wins (+0.066, n=2); phosphonate +0.050. Phase 5k mech-4 holds (decomposed-electrostatics, anion-only); CONHOH demoted to mech-anchor reference; v5.3 lead candidates pivot to CONHOMe / phosphonate heads. → artifacts/phase7i_v52_combined/SUMMARY.md
  • STRC h01 Phase 8h-lite Light Computational Evidence Package 2026-04-26 — 5 light proofs: druggability (V 1145 ų, phobic 0.61), RWM permeability (7.6× TMPA → 60% applied conc), selectivity proxy (inconclusive — needs APBS), pose-stability (K1141 NZ rigid SD 1.1 Å, lead CONHO⁻↔NZ 5.0±0.6 Å), Tanimoto vs ototoxins (max 0.127, no class motif). deliv 3→4.
  • STRC K1141 Fragment Construct Strategy — DR3 distillation: ~150-aa K1141-pocket fragment is the right unit for both biophysics (signal-to-noise on small ligand) and computation (4× faster MD than full-length 1775-aa → 100 ns local-overnight). AviTag biotinylation for oriented capture.
  • Pharmacochaperone Residence Time Criterion — DR3 distillation: slow k_off, not tight K_d, is the chaperone success metric (ER QC traversal time). H01 has no k_off number on any ligand — τRAMD on the v5.2 shortlist is the missing mechanistic axis.
  • Hydroxamic Acid Divalent Cation Liability — DR3 distillation: CONHOH warhead chelates Zn²⁺/Ca²⁺ → directly hits cochlear ion-channel + stria vascularis off-target panel. Phase 8g Vina failed to capture this (no Zn force-field term); APBS-on-Zn-loaded-pockets is the correct closure. Bioisosteric fallbacks (CONHSO₂Me, tetrazole) already in v5.2 library.
  • STRC h01 Phase 8g-v2 APBS Off-Target Rescore 2026-04-26 — FAIL, margin −6.85 kT/e. Lead anion-O ⟨φ⟩: TRPM4 +9.36 / TMEM16A +4.89 / STRC K1141 +2.51 / KCNQ4 +0.91 / Cx50 −3.02. Two surprises: (a) metals 17-62 Å away → not Zn chelation, residue-driven Coulomb; (b) STRC pose anion-O sits below Phase 5k pocket-centre +5.99 kT/e → Vina pose sub-optimal for electrostatics. deliv 4 → 3. Triggers Phase 8g-v3 site-defined re-dock + Phase 8e-v2 STRC pose-anion-O re-rank.
  • STRC Pharmacochaperone Competitive White Space 2024-2026 — DR2 distillation: 17-entry 2024–2026 otology canvass returns zero small-molecule fold-rescue competitors. Closest threat is dual-AAV gene therapy (Decibel/Regeneron AAV.104, Akouos/Lilly Seamless). Otoprotectants (SPI-1005/SENS-401/ACOU-085) and synaptopathy agents (CIL001/AC-102) share zero mechanism with E1659A. Strategic decision: COMPETE.
  • SLC26A4 H723R Pharmacochaperone Precedent — DR2 distillation: only published otology fold-rescue prior art (DNAJC14 J-co-chaperone activation rescued ER-retained pendrin H723R). Paper-discussion anchor; H01’s direct-mutant-binder mechanism gives defensible novelty vs. broad machinery-activator approach.
  • Otology Funding Pivot to Precision 2024-2026 — DR2 distillation: capital signal table — 27M Spiral Series B, €40M Cilcare Series A, FDA Otarmeni approval. Pricing benchmarks for STRC Series A; precision-genetic window open through 2026–2027.
  • Tafamidis Kinetic-Stabilization Paradigm — DR1 distillation: rate-limiting-step framing. Tafamidis (FDA 2019) raises the kinetic barrier of TTR’s rate-limiting step (tetramer dissociation). H01 mech-4 is thermodynamic (Phase 5k anion preference) but does not name which step on the E1659A QC reaction coordinate K1141 binding intercepts. Paper §3 must either name the rate-limiting step or accept the empirical-only Migalastat-style framing.
  • Migalastat Dosing-Cycle Principle — DR1 distillation: residence-time ceiling complement to floor. Migalastat works because ER 7.4 → lysosome 4.0 pH gradient drives off-rate at site of action; Afegostat failed because off-rate stayed nM at lysosomal pH and chaperone became permanent inhibitor. STRC is extracellular — no pH gradient — H01 must rely on tuned intrinsic k_off OR allosteric binding outside any stereocilin-stereocilin interface. Choice not yet made.
  • Givinostat mARC1 2 Hydroxamate Bypass — DR1 distillation: Givinostat (Duvyzat, FDA Mar 2024) is the chronic-pediatric hydroxamate regulatory precedent. Cleared via mARC1/2-mediated reduction (CYP-bypass) rather than CYP-oxidation (Lossen + hepatotoxicity). H01’s CONHOH lead inherits this script; in-vitro mARC1/2 assay is the IND-package gate. Companion to Hydroxamic Acid Divalent Cation Liability (off-target axis).
  • Ataluren Reporter-Stabilization Trap — DR1 distillation: reporter-binding artifact survived to Phase 3. Mandates reporter-free, native readout (anti-stereocilin Western / mass-spec PRM on iPSC otic-organoid lysates) for every H01 wet-lab decision-gate; refines STRC h01 Phase 8 Wet-Lab Triage SOP. In-silico analog: every binding claim from a single scoring function must pass through one independent re-evaluation (cf. Phase 7I Vina WT-bias artefact).
  • 2026-04-26 v5.3 sulfonamide class delivery (paper-grade closure):
  • STRC h01 Phase 5p v53 Acyl Sulfonamide Library 2026-04-26 — design + activation gate
  • STRC h01 Phase 5q v5.3 Acyl Sulfonamide Boltz-2 + Vina Consensus 2026-04-26 — affinity rank-1 by both methods = 1-indanyl_acylsulfonamide_SO2Me_-Cl
  • STRC h01 Phase 5e v5.3 Mut Ensemble Dock 2026-04-26 — n=20 mut-snapshot ensemble: 1-indanyl_-Cl rank-1 by mean (−0.67) and median (−1.39); 3 affinity proxies converge
  • STRC h01 Phase 5q v5.3 STRC Within-Target tauRAMD 2026-04-26 — σ_within = 1.45× → cross-target STRC:TRPM4 mathematically bounded ≤ 2.9× ≪ 5× gate; v5.3 kinetic-selectivity rescue falsified pre-emptively on STRC alone (TRPM4 v5.3 dock/τRAMD skipped, ~3 h saved); Figure 4 rendered (paper_figure4.{png,svg})
  • STRC h01 Phase 8c v5.3 ADMET-AI Triage 2026-04-26 — 2/3 fully clean; affinity-lead 1-indanyl_-Cl has 1 borderline CYP3A4_Veith flag (90.4 vs 90.0 gate); hERG band 65–69, no liability separation
  • STRC h01 Phase 5m TRPM4 Cross-Target tauRAMD 2026-04-26 — v5.2 cross-target measurement that anchored the lemma (observed STRC:TRPM4 = 1.08–1.52× vs predicted ≤ 2.4×); together with Phase 5q v5.3 closes §2.6 of the paper as “closed-by-bound” for both classes
  • STRC h01 State Audit 2026-04-26 — read-only audit reconciling hub/log vs Phase 5m TRPM4 closure
  • ELX-02 In Vitro Clinical PBPK Disconnect — DR1 distillation: in-vitro→clinic gap is owned by tissue partitioning, not affinity. ELX-02 had perfect organoid efficacy and failed Phase 2 CF because the molecule partitions to kidney, not lung. H01 has RWM permeability (STRC h01 Phase 8h-lite Light Computational Evidence Package 2026-04-26 §2) but no cochlear-compartment PBPK model — basal→apical perilymph diffusion + endolymph crossover + hair-cell-ER deposition unmodeled. Add P1-light closed-form ODE PBPK on the lead before any wet-lab capital commits.
  • Phase 8h-lite #7 cochlear PBPK ODE (2026-04-26) — artifacts/phase8h_lite/result_07_cochlear_pbpk.md. 8-compartment ODE (DEPOT/MEC/PER_B/PER_A/ENDO/HC_CYT/HC_ER/BLOOD) on the lead at 100 µM IT applied dose. HC_ER Cmax 0.4–1.3 µM depending on apical-membrane uptake bracket (30–300 min t½). Default-apical scenario gives 0% time-above-1-µM-EC over 72 h. Bottleneck = eustachian-tube clearance from MEC (k = 1.16e-2 /min) is ≈ 11 000× faster than RWM crossing (k = 1.0e-6 /min). PER_A unreached (Cmax 3e-5 µM). deliv-3 ceiling held independently from delivery side (Phase 8g-v2 was selectivity side); three concrete improvement levers (10× higher dose, +3× P_RWM via permeation enhancer, sub-µM Kd via v5.3) widen window 30–100×.
  • Phase 8h-lite #8 K1141 interface map (2026-04-26) — artifacts/phase8h_lite/result_08_k1141_interface_map.md. Phase 5d snap_010 1775-residue full-length E1659A. K1141 in central FN3-like domain, E1659A in C-terminal ZP-like domain — 13.91 Å apart in 3D, different domains. K1141 partially-buried (SASA-proxy 120) with no surface run ≥ 5 contiguous residues nearby — not on a canonical partner-binding interface. Direct architectural analog of CFTR F508del + Elexacaftor (allosteric pocket distinct from mutation site). Migalastat Dosing-Cycle Principle design constraint passes: chaperone bound at K1141 unlikely to disrupt tectorial-membrane assembly. Slow k_off shifts from “double-edge” to “pure asset” → Tafamidis-style design space.
  • STRC E1659A QC Rate-Limiting Step Lit Gap-Map — DR1 follow-on: structured retrieval queue of canonical ERAD-timing literature (Hebert/Molinari calnexin cycle, Olzmann ERAD review, Ward & Kopito 1994 F508del t½ 30 min) + STRC interactome refs (Verpy 2001/2008, Kammerer 2012, Lukashkin 2012). Stereocilin ERAD timing unmeasured; F508del CFTR is the closest characterised ECM-class missense proxy. τ-floor for τRAMD design = 60 min (2× F508del). Rate-limiting step most likely candidate: extended calnexin retention → EDEM mannose-trimming clock.
  • STRC h01 Phase 8g-v3-lite + 8h-lite 9 Pocket Max Phi + Dose Sweep 2026-04-26 — gate diagnostic + dose-escalation rescue. Phase 8g-v3-lite (resample of existing 8g-v2 / 7i dx grids with solvent-accessibility mask): Phase 8g-v2 FAIL is residue-driven on both lead variants. STRC pocket top-10 +21.90 (CONHOMe) ≤ TRPM4 +24.39 → margin −2.49 kT/e; CONHOH +29.95 ≤ TMEM16A +35.19 → −5.24 kT/e. Site-defined re-dock cannot flip verdict (would lift STRC pose-anion to ≤ pocket ceiling; off-target ceiling higher). Phase 8g-v3 full re-dock STOPPED. τRAMD on v5.2 shortlist promoted P1 → P0 (kinetic-selectivity escape hatch load-bearing). Phase 8h-lite #9 (PBPK dose-escalation sweep, 100 µM / 1 mM / 10 mM × fast/default/slow apical): 1 mM IT dose closes therapeutic window across all apical brackets (94-97 % time HC_ER ≥ 1 µM) without breaching cytosol safety ceiling (0 % HC_CYT ≥ 50 µM); 10 mM is safety cliff (66-94 % cytosol breach in fast/default). 1 mM locked as reference dose (well within IT pharmacy precedent: dex IT 10-60 mM). Deliv-3 ceiling on exposure axis liftable purely through dose escalation. Selectivity gate remains the binding constraint.
  • STRC h01 Phase 5l + 5m Smoke Fragment AF3 + tauRAMD Pipeline 2026-04-26 — AF3 K1141 fragment ladder + τRAMD pipeline validation. Phase 5l: 8 AFS jobs (4 lengths × WT/E1659A) submitted/downloaded via alphafold-server skill (Playwright MCP) in 2 min wall + 9 min download. Strict 3-criterion gate FAIL on whole-frag-Cα RMSD across all 8 (floor 4.87 Å — AF3 folds single-domain fragments without cross-domain context). K1141-ring local geometry preserved: 151_e1659a ring RMSD 0.97 Å, pocket pLDDT 78.7, pTM 0.65. Relaxed gate (ring-only fidelity) → 151_e1659a winner. Phase 5m smoke: end-to-end τRAMD pipeline validated on Phase-5d-truncated 151-aa fragment + lead adamantyl-CONHOMe-Cl (45 714 atoms, OpenCL Metal). UNBOUND at MD step 8950 = 17.9 ps biased MD under 14 kcal/(mol·Å) bias; ligand COM drifted 4.07 nm to maxDist threshold. ~10 min wall total (build + 100 ps NVT equil + 17.9 ps biased). Pipeline-validated; 7 lessons captured (am1bcc fallback to Gasteiger, PDBFixer for hand-truncated fragments, charge_from_molecules via template_generator_kwargs, RAMDSimulation properties/method gotchas, Apple Silicon Metal-OpenCL benchmark ~5 ps biased MD/min). One replica is not statistically meaningful — production = 10 replicas × 14 v5.2 shortlist + 2 controls on AF3-folded 151_e1659a substrate.
  • STRC h01 Phase 5n-lite Calnexin Retention NEGATIVE 2026-04-26 — NEGATIVE result for calnexin extended-retention as rate-limiting step. STRC has 14 NX[ST] sequons total; 0 in C-terminal ZP-like 1501-1771 where E1659A lives; nearest sequon (N1179, NLT motif) is 29.8 Å from E1659 — outside ~25 Å calnexin engagement radius. E1659A creates 0 / destroys 0 sequons — does not perturb N-glyc landscape. Mannose-trimming-clock mechanism cannot operate on a domain calnexin doesn’t see. Re-ranks rate-limiting-step candidates: ↓ calnexin extended-retention; ↑ HRD1/SEL1L core ERAD; ↑ ER-phagy; ↑ BiP/Grp78 retention. τ-floor 60 min holds (Ward & Kopito 1994 F508del ERAD t½ × 2×) but mechanism gating it pivots from calnexin-cycle to BiP-cycle / HRD1-recognition. Pharmacochaperone binding at K1141 is even safer than Migalastat Dosing-Cycle Principle flagged — K1141 is in central FN3-like (4 nearby sequons), not on the ZP-like fold disordered by E1659A.
  • STRC h01 Phase 5p v53 Acyl Sulfonamide Library 2026-04-26 — v5.3 weakly-anionic library design + RDKit triage. Acyl sulfonamide is canonical hydroxamate bioisostere (DR4): pKa 4–5, charge delocalised across C=O + 2× S=O + N (4 atoms vs CONHO⁻ single-O) → predicted 2-3× reduction in Coulomb pull on cationic off-target pocket interiors. 12 SMILES (2 heads × 2 bodies × 3 tails). 6/12 PASS all gates (Lipinski + TPSA ≤ 100 + mono-anion). All -CN tails fail TPSA (111.4 > 100); two -CF3+SO2CF3 fail Lipinski MW. Top-3 next-gen leads: 1) 1-indanyl_acylsulfonamide_SO2Me_-Cl MW 415.9 logP 1.48; 2) adamantyl_acylsulfonamide_SO2Me_-Cl MW 434.0 (direct head-swap of v5.2 lead); 3) adamantyl_acylsulfonamide_SO2Me_-CF3 MW 467.5. Activation gate: Boltz-2 + Vina + APBS pipeline only triggers if Phase 5m τRAMD STRC:TRPM4 ratio < 5× on v5.2 shortlist. 4 ERAD-timing PDFs retrieved by sci-hub: Ward & Kopito 1994 (DOI corrected), Lukacs 1994, Hebert 1996, Molinari 2007 — in ~/BookLibrary/incoming/.
  • STRC h01 Phase 5m Production tauRAMD Ranking 2026-04-26 — Production τRAMD on v5.2 mut-prefer + mech-anchor shortlist, 25/25 UNBOUND. 5 ligands × 5 replicas on Phase-5d-truncated 151-aa K1141 fragment (substrate switch from AF3-folded forced by 109k-atom OpenCL SIGSEGV; ring RMSD 0.97 Å between substrates means swap clean). Final ranking by τ̄ (ps): CONHOMe-CN 26.1 ± 16.6 (top, with one 55-ps outlier replica; median 18.7 essentially ties lead); 4-F-biphenyl-phosphonate-CN 21.1 ± 5.4; CONHOMe-Cl LEAD 19.6 ± 9.6; 1-indanyl-phosphonate-CF3 19.0 ± 4.2; CONHOH mech-anchor 15.4 ± 1.0 (shortest, tightest). Three load-bearing findings: (1) CONHOH confirmed shortest residence time → independent kinetic-axis validation of Phase 7I CONHOH→mech-anchor demotion (lead pivot to CONHOMe-Cl now data-grounded on Boltz-2 + APBS + τRAMD); (2) CONHOMe-CN edges out as top τ̄ — Phase 8h-lite #6 had flagged it as marginal RWM but on 1 mM IT dose-escalated regime the kinetic gain partially compensates (still not the lead based on integrated triage); (3) within-STRC τ-spread 1.7× falsifies the kinetic-selectivity-via-existing-head-group rescue hypothesis — same-class ligands cannot achieve 5× cross-target discrimination (mathematically bounded < 3.4× since inter-target factor < 2× for same-charge-class ligands). v5.3 acyl-sulfonamide pipeline ACTIVATED as the next heavy-queue P0. 5 SIGSEGV / parser-race bugs debugged in pipeline build (subprocess-per-replica + parent-side log parse + Gasteiger-charge fallback + single-call run_RAMD_sim + Phase-5d-truncated substrate). Caveats: N=5 small; no off-target; Gasteiger not am1bcc.

deep research

Translational / context surveys. Each is a self-contained markdown file under artifacts/deep-research/. Citation markers [1][2][3][4] are placeholders awaiting bibliography attachment — verify before paper-quoting.

  • DR1 — Pharmacochaperone Clinical Precedents → artifacts/deep-research/DR1_pharmacochaperone_precedents.md
  • DR2 — Genetic Hearing-Loss Small-Molecule Landscape 2024–2026 → artifacts/deep-research/DR2_genetic_hearing_loss_landscape.md
  • DR3 — CRO / Wet-Lab Vendor Menu for Pharmacochaperone Handoff → artifacts/deep-research/DR3_cro_wet_lab_handoff.md
  • DR4 — Hydroxamic Acid + 2-Amino-Quinoline-3 IP Landscape and Hidden Toxicity → artifacts/deep-research/DR4_hydroxamic_aminoquinoline_ip_tox.md
  • DR5 — Intratympanic / Round-Window Small-Molecule Delivery — State of the Art 2024–2026 → artifacts/deep-research/DR5_intratympanic_delivery_state_of_art.md (cleaned 2026-04-26 — 17 blob placeholders decoded)

scripts

See STRC Computational Scripts Inventory § Hypothesis 1.

log

h01 log

cross

Connections

3 items under this folder.