Design, Synthesis, and Anti-Osteoporotic Characterization of Arginine N-Glycosylated Teriparatide Analogs via the Silver-catalyzed Solid-Phase Glycosylation Strategy

In spite of effective antiosteoporosis potency, teriparatide, a bone-building agent approved by the FDA (Food and Drug Administration), was proven to exhibit various side effects. In our previous work, we developed a universal strategy for synthesizing arginine N-glycosylated peptides termed silver-promoted solid-phase glycosylation (SSG) strategy. However, it is unknown whether the SSG strategy can be applied in the peptide drug design. Herein, we first reported the optimization of teriparatide via SSG strategy. Using Arg20 and/or Arg25 as the modifying positions, three series of arginine N-glycosylated teriparatide analogs were successfully synthesized, of which the introduced sugar groups included glucose, galactose, mannose, rhamnose, ribose, 2-acetamino-2-deoxy-glucose, xylose, lactose, and maltose. Among the 27 arginine N-glycosylated derivatives, Arg20-xylose and Arg25-maltose teriparatide analogs, termed PTH-1g and PTH-2i, respectively, indicated enhanced serum stability and significantly improved antiosteoporotic activities in vitro and in vivo compared with the native counterpart. They may serve as effective therapeutic candidates for treating osteoporosis.