The SARS-CoV-2 spike (S) protein binds to the ACE2 receptor on human cells to enable viral entry. Researchers at Northwestern University have pinpointed a promising site on this protein that, when modified, could significantly weaken this critical interaction.
Since SARS-CoV-2 emerged, the surface (S) protein has been the most studied viral component. It attaches to the angiotensin-converting enzyme 2 (ACE2) receptor, allowing the virus to enter host cells. The receptor-binding domain (RBD) at the protein's tip makes direct contact with ACE2.
In a peer-reviewed study published in ACS Nano on August 2, 2020, Northwestern University scientists identified another key area just 10 nanometers from the RBD. Modifying this site, they found, could impair RBD-ACE2 binding.
The team focused on the polybasic cleavage site—comprising three arginines and one alanine, which carries a positive charge and is cleaved by the enzyme furin to activate viral fusion with host cell membranes. They compared RBD-ACE2 binding in the wild-type S protein against two mutants with altered cleavage sites. The first mutant lacked amino acids at this site, reducing interactions by 36%. The second, with two amino acids replaced, showed a 20% drop.
These findings demonstrate that changes outside the RBD can diminish the protein's infectivity. The researchers recommend therapeutically targeting this polybasic site. They also synthesized a short peptide of four negatively charged amino acids, achieving a 41% reduction in hydrogen bonds—laying groundwork for treatments that disrupt RBD-ACE2 binding.
Importantly, this work remains theoretical, with no in vitro testing conducted yet. The team hypothesizes that weakening these interactions could curb viral infectivity.
