This article and associated images are based on a poster originally authored by Lalan Kumar, Nico Boback, Badri Parshad, Marlena Schlecht, Thorsten Wolff, Anil Kumar Sahoo, Andreas Hocke, Daniela Niemeyer, Daniel Lauster and Sumati Bhatia and presented at ELRIG Drug Discovery 2025 in affiliation with Swansea University, Institute for Chemistry and Biochemistry, Harvard Medical School, Robert Koch Institute, Charité-Universitätsmedizin Berlin and Freie Universität Berlin.
This poster is being hosted on this website in its raw form, without modifications. It has not undergone peer review but has been reviewed to meet AZoNetwork's editorial quality standards. The information contained is for informational purposes only and should not be considered validated by independent peer assessment.
Heteromultivalent dual action glycosystems against influenza A virus infections
Binding and release inhibition. (SA = Sialic acid, ZA = Zanamivir, HA = Hemagglutinin, NA = Neuraminidase). Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Here, we demonstrate the concerted inhibition of different IAV strains using a low-molecularweight dual-action linear polymer. Polyglycerol-based scaffolds stand out due to their excellent water solubility, biocompatibility, and chemical versatility, making them particularly suitable for a wide range of biological applications - from drug delivery to bioengineering. These polymers can be readily modified with various functional units, enabling targeted interactions with specific molecules or surfaces. A major advancement in the field of antiviral polymers is the development of linear polyglycerol (LPG)-based heteromultivalent polymers functionalized with both 6′-sialyllactose (SA) and zanamivir (ZA). These polymers are engineered to simultaneously target two key surface proteins of the influenza A virus (IAV): hemagglutinin (HA), which mediates viral attachment to host cells, and neuraminidase (NA), which facilitates the release of new viral particles. Conjugation of these two ligands on a single polymer chain yields heteromultivalent polymers with potent antiviral activity via a dual-action mechanism. The 6′-sialyllactose moiety mimics natural sialic acid receptors, enhancing HA binding, while zanamivir inhibits NA activity, thereby blocking viral replication. Regardless of IAV subtype, binding inhibition studies indicate that heteromultivalent polymers exhibit superior virus adsorption compared to their homomultivalent counterparts. Our results demonstrate that the optimized presentation of ZA and SA on the PG backbone can efficiently inhibit the propagation of various IAV strains at very low nanomolar concentrations in vitro, achieving >99.9 % infection inhibition - approximately 10,000 times more effective than the commercial ZA drug. Building on this strategy, multivalent sialosides have also shown 500-fold stronger binding affinity against SARS-CoV-2 than highly sulfated analogs, underscoring the importance of leveraging sialoglycan-based designs for antiviral applications.
Synthesis of ZA-alkyne and SL-alkyne. Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Synthesis of SA-alkyne and LPG. Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
NA inhibition. Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Hemagglutinnation inhibition. Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Infection inhibition. Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Polysialosides vs. Polysulphates: Synthesis and inhibition of SARS-CoV-2
Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Both polysialosides and polysulfates are known to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. However, a comprehensive site by site analysis of their binding affinities and potential synergistic antiviral effects have not been performed. Here, we report on the synthesis of polysialosides with nanomolar binding affinities to spike proteins of SARS-CoV-2 in solution using microscale thermophoresis. The dendritic polyglycerol based polysialosides bind to SARS-CoV-2 at low nM concentrations which is ~500 times stronger than the high density polysulfated analog. In fact, the presence of sulfate groups in a heteromultivalent compound weakens the binding to spike proteins. A polycarboxylated analog does not bind to SARS-CoV-2, ruling out that the interaction of polysialoside is simply driven by electrostatics. Explicit-solvent all-atom molecular dynamics simulations and ensemble docking studies support the conclusion that sialosides interact stronger than sulfates for their binding with RBD of SARS-CoV-2. Notably, our most affine binder inhibits SARS-CoV-2 (WT, D614G) replication up to 98.6 % at 0.5 μM.
Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Binding affinity analysis using microscale thermophoresis (MST). Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Explicit-solvent atomistic MD simulation and molecular docking studies. Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Entry inhibition (A) and replication inhibition (B,C). Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Explicit-solvent atomistic MD simulation and molecular docking. Image Credit: Image courtesy of Lalan Kumar et al., in partnership with ELRIG (UK) Ltd.
Conclusions
The development of heteromultivalent polyglycerol-based polymers functionalized with both 6′-sialyllactose and zanamivir represents a significant advancement in antiviral polymer design. By targeting both hemagglutinin and neuraminidase on the influenza A virus, these dual-action polymers exhibit remarkable antiviral efficacy, achieving
>99.9 % inhibition at nanomolar concentrations-vastly outperforming conventional monotherapies. The success of this strategy highlights the critical role of multivalency and precise molecular architecture in enhancing virus-binding affinity and blocking replication. Furthermore, the promising application of sialoglycan-based multivalents
against SARS-CoV-2 suggests a broad potential for this platform in developing next-generation antiviral agents.
References
- Badri Parshad, et al. (2023). Dual-Action Heteromultivalent Glycopolymers Stringently Block and Arrest Influenza A Virus Infection In Vitro and Ex Vivo. Nano letters, 23(11), pp.4844–4853. https://doi.org/10.1021/acs.nanolett.3c00408.
- Khatri, V., et al. (2025). Polysialosides Outperform Sulfated Analogs for Binding with SARS-CoV-2. PubMed, pp.e2500719–e2500719. https://doi.org/10.1002/smll.202500719.
- Cuellar-Camacho, J.L., et al. (2020). Quantification of Multivalent Interactions between Sialic Acid and Influenza A Virus Spike Proteins by Single-Molecule Force Spectroscopy. Journal of the American Chemical Society, 142(28), pp.12181–12192. https://doi.org/10.1021/jacs.0c02852.
- Stadtmueller, M.N., et al. (2021). Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses. Journal of Medicinal Chemistry, 64(17), pp.12774–12789. https://doi.org/10.1021/acs.jmedchem.1c00794.
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Last Updated: Nov 27, 2025