Late-Stage Solubilization of Poorly Soluble Peptides Using Hydrazide Chemistry.

A novel late-stage solubilization of peptides using hydrazides is described. A solubilizing tag was attached through a selective N-alkylation at a hydrazide moiety with the aid of a 2-picoline-borane complex in 50% acetic acid-hexafluoro-2-propanol. The tag, which tolerates ligation and desulfurization conditions, can be detached by a Cu-mediated selective oxidative hydrolysis of the N-alkyl hydrazide. This new method was validated through the synthesis of HIV-1 protease.