This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Fibrinogen, the abundant plasma protein best known for forming blood clots, may play a second and far less benign role during SARS-CoV-2 infection: acting as a molecular bridge that simultaneously hides the virus from neutralizing antibodies and delivers it to the cells lining blood vessels. That is the hypothesis put forward by Saroj Kumar Panda (Department of Chemistry and Biochemistry, University of Texas at Arlington), Shashi Singh, and Parth Sarthi Sen Gupta (School of Biosciences and Bioengineering, D Y Patil International University, Pune) in a Viewpoint article published in ACS Pharmacology & Translational Science.
The proposal offers a single mechanistic explanation for two features of COVID-19 that have long been treated as separate problems: the virus's ability to evade immunity and the vascular damage, microclotting and inflammation that characterize severe disease and long COVID. SARS-CoV-2 is generally described as entering cells through the ACE2 receptor. But the spike protein carries clusters of positively charged lysine and arginine residues in its N-terminal domain (NTD) and receptor-binding domain (RBD).
In contrast, human fibrinogen is negatively charged at physiological pH. The authors argue this electrostatic attraction is more than incidental chemistry. When fibrinogen binds the spike NTD, it can mask antigenic sites, providing a molecular shield against antibody detection.
At the same time, the other end of the fibrinogen molecule, its gamma chain, engages endothelial receptors including the integrins αvβ3 and α5β1, platelet receptor GPIIb/IIIa and ICAM-1. The result is a tether with the virus on one end and the blood vessel wall on the other. To test whether the idea was structurally plausible, the team ran molecular docking studies.
In their preliminary results, γ-fibrinogen bound to the spike NTD appeared to open up the RBD and NTD, making the RBD's RGD motif more accessible to integrins: Integrin binding strengthened to a HADDOCK score of −127 ± 6 kcal/mol with fibrinogen present, compared with −109.4 ± 4.9 kcal/mol without it. Binding to ACE2 moved the opposite way. Spike bound ACE2 more strongly when fibrinogen was absent (−122 ± 4.6 kcal/mol) than when the complex had formed (−98.1 ± 4.8 kcal/mol).
Taken together, the simulations suggest fibrinogen may not merely coat the virus but reshape it, nudging SARS-CoV-2 away from the classical ACE2 route and toward integrin-mediated entry into endothelial cells, the pathway most closely tied to inflammation and vascular injury. The authors note that fibrinogen's alpha and beta chains are primarily engaged in fibrin polymerization and interact little with endothelial receptors. The gamma chain, by contrast, is built for exactly the anchoring the model requires, which may explain why spike appears to prefer it.
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