Controlled Synthesis of Sulfated Glycopolypeptides as Heparin Mimics via N-Carboxyanhydride ROP for Anticoagulant Property.

Sulfated glycosaminoglycans (GAGs) play important roles in a number of physiological and pathophysiological processes, including the coagulation cascade, tumor growth inhibition, viral transmission, and antioxidation. Heparin, a naturally occurring, highly sulfated GAG, remains widely used as a clinical anticoagulant. However, risks of contamination, variable pharmacological response, and its adverse side effects have motivated the development of synthetic alternatives. Earlier reports of heparin-mimicking polymers have focused on either incorporating sulfate groups via postpolymerization methods or polymerizing free sulfonic acid-containing monomers via RAFT and ROMP. Synthesis using more sensitive polymerization techniques such as ATRP, NMP, and NCA-ROP, which require polymerization of protected sulfate-containing monomers, remains challenging and largely unexplored. Herein, we report a novel synthetic methodology to prepare mannose-6-sulfate (M6S)-based glycopolypeptides as a structural mimic of heparin. Initially, the protected sulfate group was introduced, particularly at the 6-position of mannose, and an M6S-based N-carboxyanhydride (NCA) monomer was prepared. Further, the protected glycopolypeptides were synthesized via NCA-ROP techniques. The fully water-soluble sulfated M6S glycopolypeptides, subsequently obtained after deprotection steps, exhibited minimal cytotoxicity toward mammalian cells and negligible hemolytic activity, underscoring their potential suitability for biomedical applications. Furthermore, both aPTT and PT assays indicate that these synthetic materials can act as anticoagulants by significantly prolonging clotting times with performance comparable to that of heparin. The control mannose glycopolypeptides exhibited no activity, demonstrating the importance of sulfate groups in achieving anticoagulation. The mechanistic investigations elucidated the anticoagulation pathway to be dependent on factors IIa and Xa. This methodology of developing sulfated glycopolypeptides might bring in more valuable therapeutics for antiviral or anticancer materials.