A cell-surface sugar guides coronavirus entry

Researchers used high-resolution light microscopy to image individual virus particles and surface receptors directly. They found that the virus does not begin by binding ACE2. Instead, it first attaches to clusters of heparan sulfate, chains of sugar molecules that project outward from the cell surface.

Only after this initial docking does ACE2 play its role in allowing the viral genetic material to enter the cell interior. The study, published in eLife, revises the established model of how SARS-CoV-2 gains entry into cells.

Clusters as docking stations

Heparan sulfate clusters consist of groups of roughly six to one hundred and thirty-seven molecules that project between sixty and four hundred nanometres above the plasma membrane. Only about one such cluster exists per six square micrometres of cell surface. The virus selectively seeks out these clusters as its first point of attachment, before proceeding to use ACE2 downstream.

This mechanism is not unique to SARS-CoV-2. Heparan sulfate is known to interact with many other viruses, though it was traditionally viewed as a weak accessory receptor rather than a primary attachment mediator. The new findings suggest it plays a more central role than previously recognised.

Therapeutic implications

The researchers tested pixantrone, a clinically approved drug that binds heparan sulfate and blocks viral attachment sites. In laboratory experiments using human airway cells and the Omicron JN.1 subvariant, this strongly inhibited infection. These are laboratory results; whether pixantrone is effective as a treatment in people with COVID-19 has not been established. From an aging perspective, the mechanism is of broader interest because heparan sulfate patterns on cell surfaces change with age, potentially affecting how cells respond to viral challenge.

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