Fig 1.

Attachment of drug molecules as cargo to a carrier cell-penetrating peptide (CPP) through a readily cleavable bond for release of the drug in the target cell. For peptidolytic stability, a D-α-peptide (A) or a β-peptide (B) derivative can be employed. Instead of covalent attachment, counterion activation has been demonstrated previously for carboxylate salts (C) and was realized for the first time with a phosphonate salt (D) in the present study. Structures for fosmidomycin, FR-900098, FAM-octaarginine amide (compound 1), fosmidomycin-octaarginine salt (compound 2), and fosmidomycin-octaarginine covalent conjugate (compound 3) are shown.