Pyridium-π Interaction Preserved the N,S-benzylidene Thioacetals (NTDs) in Acidolysis Enabling Efficient Protein Chemical Synthesis

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The development of chemical protein synthesis enables access towards peptides and proteins with atomic-level precise modifications. However, the synthesis of aggregation-prone peptides and proteins remains a major challenge in both solid-phase peptide synthesis (SPPS) and chemical ligation. Here, we report a general strategy employing N,S-benzylidene thioacetal dipeptides (NTDs) as versatile aggregation-disrupting building blocks both on and off resin. These NTDs can be robustly prepared in one pot with high yield, covering Xaa-Cys, Xaa-Pen sites, and the D-configuration ones. In addition, NTDs are directly compatible with SPPS without any prior deprotection steps, enabling rapid installation of multiple N,S-benzylidene thioacetal motifs. More importantly, we discovered a picolinoylation-based strategy to address the acid lability of NTD, which preserves the scaffold during global deprotection through pyridium-π interaction and can be selectively removed on demand. This approach effectively suppresses aggregation both on-resin and in-solution, facilitates macrocyclization, and permits selective manipulation of cysteine residues during multi-fragment assembly. As a demonstration, we achieved the chemical synthesis of the hydrophobic protein human erythropoietin (hEPO) via a convergent route with native chemical ligation and serine/threonine ligation incorporating the NTD chemistry.

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