Easy‐to‐Attach/Detach Solubilizing‐Tag‐Aided Chemical Synthesis of an Aggregative Capsid Protein

A solubilizing Trt‐K 10 tag was developed for the effective chemical preparation of peptides/proteins with low solubility. The Trt‐K 10 tag comprises a hydrophilic oligo‐Lys sequence and a trityl anchor, and can be selectively introduced to a side chain thiol of Cys of deprotected peptides/proteins with a trityl alcohol‐type introducing reagent Trt(OH)‐K 10 under acidic conditions. Significantly, the ligation product in the reaction mixture of a thiol‐additive‐free native chemical ligation can be modified directly in a one‐pot manner to facilitate the isolation of the product by high‐performance liquid chromatography. Finally, the Trt‐K 10 tag can be readily removed with a standard trifluoroacetic acid cocktail. Using this easy‐to‐attach/detach tag‐aided method, a hepatitis B virus capsid protein that is usually difficult to handle was synthesized successfully.