Heparan sulfate (HS) can act as an attachment receptor for many different animal viruses. Virus binding to HS occurs through electrostatic interactions between the negatively charged sulfate and carboxyl groups of HS with positively charged amino acids present in viral proteins. Soluble heparin, a glycosaminoglycan related to HS, can inhibit infection by many viruses, but clinical use of heparin is limited by its anticoagulant activity.
Our rationale for the dendritic design of HS mimetics [1,2] was based on retention of the capacity for polyvalent interactions exhibited by HS and other GAGs that enables ‘velcro-like’ interactions in molecular recognition. While traditional drug discovery has focused on small molecules targeting a single binding site, many biological systems rely on multivalent engagement across multiple domains. The individually weak affinities of each subunit are markedly enhanced when presented in a repeated, spatially organized manner, creating a synergistic clustering effect. Moreover, our dendrimer-based HS mimetics are single chemical entities, a property that distinguishes them from many synthetic polyvalent compounds and polymers that can exist as complex mixtures.
In our work exploring the spatial dimensions of multivalent ligand design, we systematically elongated carbon linkers to modulate the size of molecular scaffolds of HS mimetics revealing a critical “Goldilocks zone” in linker length. We established that the balance of geometry and flexibility was the key to tuning bioactivity in clustered systems.
We investigated inhibition of respiratory syncytial virus (RSV) and herpes simplex virus type-1 (HSV-1) by a set of tri- and tetrameric dendritic HS mimetics. Several of our compounds exhibited sub-micromolar inhibition of both viruses when used as receptor decoys in assays of virus entry and a lead compound inhibited the cell-to-cell spread of RSV in vitro and RSV-mediated membrane fusion. Additionally, we observed synergistic effects when a HS mimetic was used in combination with clinical antiviral remdesivir.
We have identified the anti-SARS-CoV potential of HS mimetics that demonstrated increased potency against the more recent Omicron lineage. We also observed strong drug synergism between one HS mimetic and nirmatrelvir in combination against SARS-CoV-2 BA.1. We showed that HS mimetics are a valuable class of host-targeted antivirals with the potential to remain effective despite the continual emergence of new SARS-CoV-2 variants [3].
The dual ability of HS mimetics to block viral entry and modulate inflammation positions them as antiviral agents that could reduce both infection rates and disease severity [4].
The solubility, lack of anticoagulant activity and antiviral potency of these dendritic HS mimetics make them a promising new class of broad-spectrum antiviral therapeutics.