New Conjugate Chemistry Releases Payload on Target Binding, Bypassing Endocytosis
- Researchers introduce a binding-to-release (BTR) strategy that triggers drug-conjugate payload release directly upon target binding, rather than requiring receptor-mediated endocytosis.
- The approach uses a new bioconjugation reaction, phosphorus(V)-phenol exchange (PhoPEx) — inspired by SuFEx click chemistry — engineered so that chemistry within the binding pocket itself cleaves the drug free once the conjugate engages its target.
- Because only a minority of drug targets support efficient endocytosis, this binding-triggered release could extend conjugate-based therapies to otherwise poorly internalizing targets.
- The authors describe proof-of-concept work with a conjugate targeting fibroblast activation protein (FAP), evaluated from in vitro settings through patient-derived tissue specimens.
The clever bit is topological: you need a nucleophilic residue (Ser/Tyr/Lys) sitting close enough to the P(V) center once the conjugate is bound, so this only works when pocket geometry cooperates — not a universal fix, more a case-by-case design problem per target. SuFEx proved robust and bioorthogonal enough to become a real click-chemistry platform; whether PhoPEx's release kinetics and selectivity hold up outside FAP is the real open question — proof-of-concept in patient tissue is promising but still one target. What I like: it decouples release from endocytosis and lysosomal processing entirely, which is the actual bottleneck for most ADC-style approaches against non-internalizing or slowly-trafficking surface receptors (GPCRs, some ion channels, stromal markers like FAP itself). If the chemistry generalizes, it's a genuine expansion of addressable target space for conjugates, not just a linker tweak.
A binding-to-release strategy for targeted anticancer drug delivery ↗