On December 16, 2025, Lihao Wang and their colleagues from the Key Laboratory of Marine Drugs at the Ocean University of China published an article in the journal Marine Drugs titled "Precision-Engineered Dermatan Sulfate-Mimetic Glycopolymers for Multi-Targeted SARS-CoV-2 Inhibition." This research describes the strategic design and controlled synthesis of glycopolymers that mimic the bioactive architecture of Dermatan Sulfate (DS), a glycosaminoglycan prevalent in marine invertebrates. The findings demonstrate that these precision-engineered glycomimetics function as potent, multi-targeted inhibitors capable of neutralizing multiple SARS-CoV-2 variants, including Omicron sublineages, by disrupting viral attachment and entry mechanisms.

Research Background

The field of Marine Glycobiology has long recognized the ocean as a reservoir of unique Glycosaminoglycans (GAGs). While terrestrial GAGs like heparin and DS are well-studied, their marine counterparts often possess distinct sulfation patterns, such as 2,4-O-disulfated GalNAc units or higher fucose branches, which impart superior biological activities. In the context of the COVID-19 pandemic, glycobiology has taken center stage because the SARS-CoV-2 virus uses glycans as its primary point of contact with human cells.

However, the clinical application of natural marine GAGs is often hindered by two major challenges: the "anticoagulant risk" associated with heparin-like structures and the inherent structural heterogeneity of natural extracts. DS is particularly interesting to glycobiologists because it contains L-iduronic acid (IdoA), a sugar that provides the polysaccharide chain with greater conformational flexibility compared to D-glucuronic acid-containing polymers. This flexibility allows DS to "mold" itself into the binding pockets of various proteins. By shifting from natural extraction to "precision engineering" of DS-mimetics, the authors of this study have addressed the need for reproducible, safe, and highly specific antiviral Glycoconjugates that harness the evolutionary wisdom of marine chemistry without its associated side effects.

Research Results

• Targeted Synthesis of Sulfated Galactosamine Glycomonomers and Controlled Polymerization

The cornerstone of this research lies in the sophisticated chemical synthesis of biomimetic monomers that replicate the essential epitopes of DS. DS is structurally characterized by repeating disaccharide units of L-IdoA and N-acetyl-D-galactosamine (GalNAc), typically sulfated at the C-4 position of the GalNAc residue. The authors developed a high-yield synthetic route to create sulfated GalNAc-based acrylamide monomers. By employing reversible addition-fragmentation chain transfer (RAFT) polymerization, the team achieved "precision engineering" of the resulting glycopolymers.

This technique allowed for meticulous control over the molecular weight (Mn) and the polydispersity index (PDI), ensuring that the synthetic chains were homogeneous. The innovation here is the ability to maintain the high sulfation density required for biological activity while eliminating the structural complexity and "off-target" effects associated with natural polysaccharides like heparin. The researchers successfully produced a library of glycopolymers with varying degrees of polymerization, allowing them to pinpoint the optimal chain length for maximum viral interference.

Fig.1 Preparation and characterization of diverse DS-mimetic glycopolymers. (Wang, et al., 2025)

• Broad-Spectrum Neutralization of Omicron and Delta Variants

The second phase of the study involved rigorous biological evaluation of these DS-mimetic glycopolymers against the SARS-CoV-2 virus. Utilizing pseudotyped virus neutralization assays, the researchers tested the glycopolymers against a range of variants, including the early Delta strain and the highly transmissible Omicron (BA.1 and BA.5) subvariants. The results were compelling: the precision-engineered glycopolymers exhibited nanomolar inhibitory concentrations (IC₅₀ values), significantly outperforming natural DS isolated from terrestrial sources.

A key finding in this section was the observation of a "cluster glycoside effect" or multivalency. As the chain length of the glycopolymers increased, the inhibitory potency rose exponentially, suggesting that the polymers provide a dense array of sulfated ligands that simultaneously occupy multiple binding sites on the viral surface. Furthermore, the researchers conducted cytotoxicity assays using human lung epithelial cells (Calu-3), confirming that these marine-inspired glycomimetics possess an excellent safety profile with negligible cellular toxicity even at high concentrations. This highlights their potential as biocompatible therapeutic agents.

Fig.2 Schematic diagram of DS-mimetic glycopolymer nanoparticles targeting viral particles and protecting host cells. (Wang, et al., 2025)

• Multi-Targeted Inhibition of Spike Protein and Host Attachment Factors

To elucidate the molecular mechanism behind the observed antiviral activity, the team performed surface plasmon resonance (SPR) and competitive binding assays. The research identified that the DS-mimetic glycopolymers act through a multi-targeted strategy. Primarily, the sulfated glycan chains bind with high affinity to the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein. This binding effectively "masks" the viral protein, preventing its interaction with the host cell receptor, angiotensin-converting enzyme 2 (ACE2).

Beyond simple RBD blocking, the study uncovered that these glycopolymers also interfere with the virus's reliance on host-surface heparan sulfate (HS) co-receptors. By mimicking the structure of HS and DS, the synthetic polymers compete for the same binding pockets on the viral S-protein, thereby stripping the virus of its primary docking mechanism. Additionally, the researchers explored the inhibition of heparanase (HPSE), an enzyme that the virus exploits to remodel the host's glycocalyx and facilitate viral egress. The precision-engineered glycopolymers showed potent inhibitory activity against HPSE, suggesting they block the viral life cycle at both the entry and exit stages. This dual-action mechanism is a significant innovation, as it reduces the likelihood of the virus developing resistance through single-point mutations in the Spike protein.

Fig.3 Proposed mechanism of action for DS-mimetic glycopolymers as multi-target antiviral agents against SARS-CoV-2. (Wang, et al., 2025)

Marine Carbohydrate-based Biomaterial Engineering Development Service at CD BioGlyco

Conclusion

By synthesizing precision-engineered DS-mimetic glycopolymers, the researchers have created a versatile platform for combating the ever-evolving SARS-CoV-2 landscape. The primary conclusion of the paper is that synthetic control over sulfation density and molecular weight produces antiviral agents that are more potent and safer than their natural predecessors. This research paves the way for the development of intranasal sprays or systemic glycodrugs that provide broad-spectrum protection against current and future coronaviruses.