An Integrated Solubilizing-Tag-Free Strategy for Chemical Synthesis of Mirror-Image Interleukin-6

Interleukin-6 (IL-6) stands as a therapeutically important target, and the efficient chemical synthesis of mirror-image D-IL-6 could facilitate the development of D-peptide antagonists to complement the existing repertoire of antibody-based antagonists. Herein, we report a new integrated synthetic strategy for D-IL-6 characterized by three key features: a three-segment assembly of full-length D-IL-6 via two ligation reactions; a one-pot process of low-energy visible light-induced desulfurization and acetamidomethyl (Acm) deprotection; and the mitigation of poor intermediate solubility using organic cosolvents. By minimizing operational steps, this streamlined approach enhances the overall yield of D-IL-6 synthesis compared to the previous methods and establishes a robust platform for the discovery of IL-6-targeting D-peptide therapeutics.