Development of the Thiol‐Selective Solid‐Supported Oligoarginine‐Conjugating Reagent KSH‐2

Arginine‐rich, cell‐penetrating peptides (CPPs) and oligoarginines are attractive tools for intracellular delivery of various molecules with low membrane permeability. Although a variety of labeling methods have been reported, we report here the design and synthesis of a thiol (SH)‐group selective solid‐supported octaarginine‐conjugating reagent KSH‐2. KSH‐2 was prepared by two steps including the activation of 3‐nitro‐2‐pyridinesulfenyl (Npys) resin by chlorosulfenylation and the loading of a Cys( t Bu)‐containing octaarginine unit to form an active disulfide. In model experiments using SH‐containing captopril and hexadecapeptide, solid‐supported reagent KSH‐2 efficiently gave the octaarginine‐conjugated products with a high degree of purity by only mixing and filtration. This reagent could be applied to a wide variety of SH‐containing molecules for selective oligoarginine conjugation.