STRC Research

STRC Synthetic Peptide Hydrogel HTC

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STRC Synthetic Peptide Hydrogel HTC

⚠ STATUS 2026-04-23: Tier A (backburner). Phase 3/4 compute done. Gate 3 (STRC×TMEM145 Kd) NARROWED 2026-04-23 via Dunbrack 2025 ipSAE reassessment — UM × TMEM145 GOLD ipSAE 0.591 sits in known-binder-band (NFAT-CnB 0.550 … NFAT-CnA 0.783 physiological binders); placeholder 100 nM now lit-band-consistent (Calcineurin-family 10 nM-10 µM) rather than arbitrary. Absolute Kd still requires wet-lab SPR/BLI. “Path B” (AF3-only absolute Kd calibration) closed as literature-infeasible (AF3 score bands span orders of Kd magnitude per bioRxiv 2025.04.07.647682; jcim.4c00976). One load-bearing parameter remains fully unmeasured:

  • WH2 × F-actin side-binding Kd: no canonical WH2 measurement published (G-actin Kd ~0.2 µM is well-characterized — Chereau 2005, Dominguez 2016; but F-actin side-binding mode not quantified). Scripts use WH2_KD_FACTIN_M = 5 µM assuming 25× weakening from G-actin — optimistic vs Tβ4 F-actin analog 5–10 mM.

Phase promotion to S requires: wet-lab narrowing of WH2×F-actin Kd (Phase 2c bundling assay is gate #1 per Phase 4i 5×5 sensitivity sweep). TMEM145 SPR/BLI is gate #2 — already operable-band-placed by ipSAE. Sensitivity result: f≥0.3 therapeutic window reachable on 80% of plausible Kd grid (PASS 56% + MARGINAL 24%); FAIL 20% exclusively at WH2 Kd ≈ 1 mM (Tβ4 analog floor where G-actin toxicity ceiling hits before coupling target). WH2 is the load-bearing parameter, TMEM145 is secondary. See STRC h09 Phase 4i Kd Sensitivity Sweep 2026-04-23 for sweep; STRC ipSAE Cross-Complex Reassessment 2026-04-23 for TMEM145 gate 3 narrowing; STRC h09 Parameter Provenance Audit 2026-04-23 for full audit; STRC TMEM145 Kd Experiment Plan for wet-lab gate.

Third gate (tail-91 vs 12 aa empirical RADA16 modification limit): CLOSED 2026-04-23 via STRC h09 Phase 4e_v2 Blend Scaffold. Design now specifies 5% molar blend of RADA16-tail91 in 95% plain RADA16 (φ_tail = 0.05, PASS per Frontiers 2021 Gelain-hybrid range extrapolation). Valency still 2000× excess vs putative TMEM145 site density (30×10³ sites/bundle low estimate); dose cost 3.8× vs hypothetical 100 % tail91 — still within 0.5–5.0 mg intra-tympanic tolerance.

A self-assembling peptide (SAP) hydrogel, delivered as an ear drop, can form synthetic horizontal top connectors between outer hair cell stereocilia and anchor the bundle to the tectorial membrane — replacing stereocilin’s mechanical function without any gene, virus, or cell transfection.

The hidden assumption this breaks

All mainstream DFNB16 therapy plans assume we must restore STRC protein. But STRC’s function is purely mechanical coupling. This is materials science, not molecular biology. A synthetic polymer with the right adhesion chemistry and bundle-scale dimensions can do the job.

Mechanism

  1. Payload: FDA-precedent SAP backbone (RADA16, IEIK13, or EAK16 — used in stroke neural repair, dental pulp regeneration) engineered with two functional extensions:
    • N-terminal: actin-binding peptide (from espin / fascin homolog) → hooks into stereocilia core
    • C-terminal: ZP-domain-like motif OR a short peptide aptamer that binds TMEM145 GOLD domain
  2. Delivery: aqueous gel dropped into ear canal. Round window membrane permeability bumped 5.2× by low-intensity focused ultrasound (Shih 2019, published and safe).
  3. In-situ assembly: peptide monomers (2–5 kDa) diffuse through perilymph, cross-link at stereocilia surfaces where actin and TMEM145 are concentrated, form β-sheet fibrils that mechanically couple adjacent stereocilia (row 1 ↔ row 2 ↔ row 3 + tallest row ↔ TM).

What it restores

The f parameter in STRC Stereocilia Bundle Mechanics Model — HTC coupling fraction. Model prediction: f = 0.3 recovers ABR threshold from 64 dB → 42 dB (≈22 dB rescue). f = 0.6 → ~30 dB ABR.

Computational proof path

  1. De novo peptide design — RFdiffusion + ProteinMPNN on dual-domain scaffold (actin-binding + TMEM145-binding). Target: <60 aa, β-sheet-forming, stable at pH 7.4 (endolymph).
  2. AF3-Multimer validation — designed peptide × TMEM145 GOLD + actin filament. Accept if ipTM > 0.6 on both interfaces.
  3. Coarse-grained MD (Martini3) — four-stereocilium patch with engineered SAP cross-links. Compare bundle stiffness (pN/nm) against WT STRC reference (Tobin 2019). Target: ≥60% of WT stiffness at SAP density feasible for ear-drop dose.
  4. Cochlear pharmacokinetics — Stokes-Einstein diffusion (D ≈ 150 µm²/s for 3 kDa peptide at 37 °C). Time to saturate scala tympani from RWM: ~20 min, compatible with clinic visit.
  5. Mechanical coupling to Hopf loop — plug restored f into Cochlear Amplifier as Hopf Oscillator gain model. Required f for threshold < 30 dB: ~0.4.

Why plausible

  • Self-assembling peptides (RADA16 family) are already in human use — puramatrix for surgical hemostasis, IKVAV-decorated SAPs in spinal cord trials.
  • Cochlear perilymph is benign for SAP assembly: pH 7.4, low protease activity, 150 mM Na⁺, 4 mM K⁺.
  • Mini-STRC itself is ~1,100 aa — a 60-aa synthetic replacement is 1/20 the size and manufacturable.
  • The mechanical job is low-bandwidth: stereocilia vibrate at audio frequencies but the HTC is a static stiff spring. Static mechanical coupling is the easiest failure mode to engineer.

Open questions

  1. Can a 60-aa peptide encode both actin-binding and TMEM145-binding with enough affinity? Affinity floor: Kd < 1 µM for each interface.
  2. Does SAP cross-linking interfere with stereocilia actin dynamics? Primary lit: Zhang et al. 2012 Nature (PMID 22246323) shows stereocilia shaft actin is stable over months (<10%/day incorporation); tip-localised β-actin t½ is a few hours (tips, not shaft). Earlier “48 h” figure in this note was unsourced — removed. SAP cross-linking therefore targets a mostly static actin core, which supports the mechanism (unlike dynamic cytoskeletons, treadmilling is slow enough that cross-linked SAPs don’t need to keep up with high turnover).
  3. Is TMEM145 accessible in STRC-deficient bundles, or has its expression also collapsed? Derstroff 2026 implies TMEM145 survives STRC loss transiently but long-term stability unclear.
  4. Manufacturability at pharmacy scale: solid-phase peptide synthesis of 60-mer is $1–10/mg; dose estimate 1–10 mg per ear drop.

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