Scheme 1.

Outlined is the general procedure to orthogonally incorporate a tri-Boc-protected hydrazide (HAA(Boc)₃) in peptides synthesized on resin via addition to a selectively deprotected lysine residue. Standard procedures for solid phase peptide synthesis (SPPS) can be performed before and after addition of the protected hydrazide and, in the case of PA synthesis, a palmitic acid tail is coupled following stepwise peptide synthesis. Upon cleavage from the resin, a PA containing a free hydrazide is obtained which can be purified and then condensed with the ketone of dexamethasone (blue) to form the hydrazone-linked drug conjugate, termed Dex-PA.