Bicyclic Peptide Libraries Deliver First Noncarbohydrate Inhibitors of the Hard-to-Drug Receptor Siglec-7
- Researchers used bicyclic genetically encoded peptide libraries (BiGEL) — phage-displayed peptides chemically stapled into two rings — to search for inhibitors of Siglec-7, a glycan-binding immune receptor considered notoriously hard to target with small molecules.
- Sequencing-based panning against Siglec-7 nominated hundreds of candidate peptides; a subset were confirmed as genuine binders by surface plasmon resonance and as functional disruptors of the Siglec-7:GD3 interaction by competitive ELISA, with machine learning models identifying further hits of similar potency.
- Structure-activity work showed the bicyclic ring architecture itself is essential for potency, and NMR studies located one optimized lead's binding site away from the canonical glycan-binding domain, pointing to a possible allosteric mechanism.
- Cell-based multivalent binding assays confirmed engagement with Siglec-7 but also revealed considerable nonspecific binding to receptor-negative cells, highlighting a selectivity challenge still to be resolved.
The allosteric site is the real hook here — a bicyclic peptide binding away from the canonical glycan pocket on a target everyone assumed only the carbohydrate-recognition domain was druggable gives you a completely different SAR vector than trying to out-compete sialic acid for its own pocket. That's genuinely exciting for Siglec-7. But I'd want the nonspecific binding in the cell assays resolved before getting attached to any single lead — multivalent avidity effects can paper over a mediocre core affinity, and that's exactly the kind of artifact that kills a program downstream. Bicyclics themselves are the right chemotype to bet on: synthesizable, chemically stable enough for iterative SAR, and unlike DEL small molecules they're not fighting the flat, shallow topology that's stalled every prior GBP inhibitor effort.