Reworking the DHIle Residue of α-Amanitin Yields Picomolar Trastuzumab–Amatoxin ADCs
- The team probed the δ-position of the 4,5-dihydroxyisoleucine residue in α-amanitin, a residue long assumed to drive RNA polymerase II inhibition.
- Two δ-modified analogs carry handles for direct linker attachment, so conjugation no longer has to go through other positions on the bicyclic peptide.
- Both were converted into trastuzumab conjugates that showed extremely high cytotoxicity on target-expressing cells, supporting these amatoxins as ADC payloads.
💡 Points
This is the kind of payload SAR I want more of. Amanitin's DHIle has been treated as untouchable, so finding a δ-position that tolerates substitution and doubles as a conjugation handle opens a cleaner attachment strategy than the usual lysine or Asn shuffles. I'd want to see plasma stability and bystander behaviour next, since transcription-arrest payloads live or die on therapeutic index.