UK researchers identify three novel SARS-CoV-2 binding receptors, including one matching ACE2 affinity

British researchers have identified three previously unknown receptors that the coronavirus can use to enter human cells, a discovery that may help explain why the virus affects the body in ways beyond simple respiratory infection. The team conducted an exhaustive screening of more than 8,500 human cell receptors—both those anchored to cell membranes and those that float freely in the bloodstream—looking for any that might bind to the spike protein that SARS-CoV-2 uses to breach cell walls.

The virus has long been known to rely primarily on a receptor called ACE2 to gain entry into cells, with help from a human protease enzyme called TMPRSS2 that activates the spike protein once it makes contact. But researchers have suspected for some time that other cellular doorways might exist. Previous work had identified neuropilin-1 and basigin as secondary entry routes. This new study, conducted using cell microarray technology and later confirmed through flow cytometry, found something more comprehensive: a total of 23 binding proteins for the full-length spike protein, of which 15 were membrane receptors and 8 were surface-anchored secreted proteins.

When the team narrowed their focus to proteins that showed specific, reproducible interactions with the spike protein, they identified 10 candidates. Five of these also bound to the spike protein of the original SARS virus, and two bound to MERS-CoV spike protein as well. But three stood out as unique to SARS-CoV-2: nidogen-1 (NID1), contactin-1 (CNTN1), and apolipoprotein A4 (APOA4). The discovery of APOA4 proved particularly striking. This protein, which is produced by intestinal cells and plays a central role in how the body processes fats, bound to the spike protein with nearly the same strength as ACE2 itself—the virus's primary entry mechanism.

The intestinal connection is not incidental. About 30 percent of COVID-19 patients experience gastrointestinal symptoms, a puzzle that has troubled clinicians since the pandemic began. APOA4's presence in the gut lining suggests a plausible explanation: the virus may use this protein as a secondary route into the body, potentially explaining why some patients develop digestive complications. The protein is also known to facilitate entry of hepatitis C virus, suggesting it may have a general vulnerability to viral exploitation.

The other two novel receptors point toward different vulnerabilities. NID1 is a structural protein found in basement membranes, tightly woven into the networks of laminin and collagen that form the scaffolding beneath cell layers. CNTN1 is a neuronal adhesion protein that helps build connections between nerve cells. The researchers also identified a broader family of receptors—the C-Type Lectin Domain Family 4 proteins—that show high affinity for the glycoproteins studding the viral envelope and may influence how readily the virus spreads from person to person.

The work remains preliminary. The findings have been posted on bioRxiv, a preprint server where scientists share results before peer review, and the authors themselves note that such reports should not yet guide clinical decisions or be treated as settled science. But the breadth of the screening and the confirmation of results through multiple experimental methods suggest the findings are robust. The discovery opens new questions about which tissues and cell types are most vulnerable to infection, why the virus causes such varied symptoms across patients, and whether blocking these alternative entry routes might offer new therapeutic angles. The research also underscores how much remains unknown about the basic mechanics of how this virus moves through the human body.