Concise Chemical Synthesis of O-Linked Glycans

Abstract

Despite the well-recognized role of glycosylation in regulating protein properties, the lack of homogeneous glycoprotein isoforms has hindered progress in both research and application. Here, we tackle this issue by presenting a concise, divergent synthetic route for the efficient preparation of O-linked glycoamino acid building blocks featuring regioselective 3-OH glycosylation and α-sialylation. This streamlined methodology significantly mitigates the labor-intensive challenges associated with traditional techniques and enables the creation and biological evaluation of naturally glycosylated variants of growth hormone-releasing hormone (GHRH). Notably, this study provides the first evidence that O-glycosylation substantially enhances the proteolytic stability of GHRH, highlighting the potential of our synthetic strategy to propel the field of protein O-glycosylation and its therapeutic applications forward.