A peptide that selectively disrupts a pathological α2δ-1 protein–protein interaction can reduce mechanical hypersensitivity in lumbosacral radiculopathy, without the sedation and dependence liabilities that limit gabapentinoids.

Rationale / unmet need. Lumbosacral radiculopathy is a mixed inflammatory–neuropathic condition. Gabapentinoids — the standard neuropathic-pain agents — bind α2δ-1 broadly and showed no benefit over placebo for sciatica in a major RCT (PRECISE, NEJM 2017), while carrying sedation and dependence liabilities. This motivates a more selective intervention on α2δ-1 biology rather than blanket channel modulation.

Supporting evidence (public). Prior work established that α2δ-1 drives pathological signalling through a specific protein–protein interaction beyond its classical calcium-channel role, and that a decoy peptide disrupting that interaction reduces neuropathic pain in preclinical models (Chen et al., 2018). This provides a validated mechanistic anchor and a tool-peptide starting point.

Proposed methodology. AI-guided peptide design (PeptAI) to generate developable, stable analogs of the published decoy peptide → in-vitro target-engagement and functional-disruption assays → in-vivo analgesia and tolerability in an established neuropathic-pain model, benchmarked against a gabapentinoid comparator.

What would falsify it. Lead analogs failing to disrupt the target interaction in vitro, or no dose-dependent reduction in mechanical hypersensitivity in vivo versus vehicle/comparator.

Status. Early hypothesis / fast-follower exploration, posted openly for collaboration and critique.