Mucin‐Inspired Filamentous Sulfated Copolymers Effectively Inhibit Human Respiratory Syncytial Virus (hRSV) Infectivity

Abstract Virucidal compounds capable of binding to and disrupting viruses represent a promising avenue for antiviral applications. In this study, the development of high molecular weight (≈300 kDa) dendronized polyglycerol‐based mucin‐inspired amphiphilic statistical copolymers (MIACPs) is reported using the RAFT polymerization technique. These copolymers comprise ≈30% repeat units containing aliphatic C11 carbon chains with terminal carboxylate (MIACP‐1) and alkyl (MIACP‐2) functionalities, while the remaining ≈70% of the repeat units consist of dendronized polyglycerol sulfates. Structural characterization using cryo‐electron microscopy (cryo‐EM) and small‐angle neutron scattering (SANS) reveals that MIACPs form single‐chain filamentous structures, similar to natural porcine gastric mucin (PGM). These biocompatible MIACPs exhibit strong, sulfate‐dependent inhibition of human respiratory syncytial virus (hRSV), with exceptionally low IC ₅₀ values (C = ≈0.25 µg mL ⁻¹ ). The virucidal activity is assessed using serial dilution experiments, which confirms that MIACPs demonstrate virucidal activity, indicating a very strong binding affinity of the polymers to the hRSV. In contrast, a similar molecular weight homopolymer composed solely of sulfated dendronized repeat units exhibits comparable hRSV inhibition activity but lacks any virucidal effect. Therefore, designing a statistical copolymer with ≈30% virucidal functionality is unique in that it renders the copolymer virucidal without compromising its inhibitory activity.