Sulfated Glycomimetic α-Helical Polypeptides for Antiviral Activity

In this work, we developed a library of sulfated glycomimetic polypeptides with a high sulfated degree (up to 99%) via a click reaction and sulfation modification, enabling control over the helicity, molecular weight, rigidity, and side-chain structure. Their potentials as the inhibitors of SARS-CoV-2 and common enterovirus were investigated, and the structure-activity relationship was explored in detail. The in vitro results revealed the crucial role of α-helical conformation and sulfated sugar since all the sulfated glycopolypeptides exhibited outperformed activity in suppressing SARS-CoV-2 infection with the inhibition efficiency up to 85%. Other structural properties, including the rigid chain structure and a moderate molecular weight, also contributed to blocking the viral entry into host cells. Among the sulfated glycopolypeptides, L₆₀-SG-POB showed the highest inhibition efficiency with an IC₅₀ of 0.71 μg/mL. Furthermore, these optimized sulfated glycopolypeptides were also capable of preventing enterovirus infection with the inhibition efficiency of up to 86%. This work opens new avenues for the development of synthetic polypeptides bearing sulfated sugars against SARS-CoV-2 and other viruses.