Challenges in developing broad-spectrum viral attachment inhibitors targeting heparan sulfates and sialic acids

Many distinct viruses exploit cell surface glycans, particularly heparan sulfates and sialic acids, as initial attachment factors to facilitate entry into host cells. Because these interactions are highly conserved across diverse viral families, they have long been viewed as attractive targets for the development of broad-spectrum antiviral strategies. Over the past decades, numerous approaches have attempted to block these early binding events, including genetic or enzymatic removal of glycans from the cell surface, masking of cell surface glycans, the use of engineered decoy receptors, and the development of multivalent inhibitors. Despite promising <i>in vitro</i> results, no antiviral therapy based on this mechanism has yet advanced to routine clinical use. Here, the biological roles of heparan sulfates and sialic acids in viral entry are examined, and the range of antiviral strategies designed to interfere with these interactions is discussed. The major challenges that have limited clinical translation are highlighted, including insufficient potency, potential off-target effects, the risk of resistance, and challenges related to routes of administration. Finally, recent technological advances that may help overcome these barriers and enable the development of clinically viable viral attachment inhibitors are proposed.