Researchers have described creating a new family of synthetic peptides that can prevent the SARS-CoV-2 virus from infecting cells and clumping the virus’s infectious virions (particles) together. This innovative strategy offers a different way to render viruses like SARS-CoV-2 dormant and holds promise for a new family of peptides as antivirals.
The COVID-19 vaccines’ effectiveness against the SARS-CoV-2 virus has been reduced by the quick exposures of new strains, entailing the development of new methods for preventing virus infection.
Protein-protein interactions are believed to resemble a lock and a key frequently. A synthetic peptide that imitates competes with and blocks the “key” from binding to the “lock” or vice versa can interfere with this interaction. Utilizing this strategy, Scientists at the Indian Institute of Science (IISc), in alliance with the CSIR-Institute of Microbial Technology researchers, have created peptides that can bind to and prevent the spike protein on the surface of the SARS-CoV-2 virus. This binding was further and thoroughly characterized with cryo-electron microscopy (cryo-EM) and other biophysical techniques.
The produced peptides have helical, hairpin-like forms and can each interact with another peptide of a similar type to form a dimer. Each dimeric “bundle” offers two “faces” to interact with two target molecules. According to the published study, the two faces would attach to two different target proteins, locking all four of them together in a complex and inhibiting the targets’ ability to function. The researchers chose to test their theory by concentrating on the inter-linkage between the Spike (S) protein of SARS-CoV-2 and ACE2 protein, the SARS-CoV-2 receptor in human cells, using a peptide labelled SIH-5.
The S protein is a trimer, a construct composed of three identical polypeptides. Each polypeptide contains an RBD that interacts with the ACE2 receptor on the surface of the host cell. This interaction aids in the entry of the virus into the cell.
In order to prevent the RBD from adhering to human ACE2, the SIH-5 peptide was developed. When a SIH-5 dimer came into contact with an S protein, one face of the dimer was strongly attached to one of the three RBDs on the trimer of an S protein, and the other face was tied to an RBD from a separate S protein. This ‘cross-linking’ allowed the SIH-5 to block both S proteins at the same time. The S proteins that SIH-5 appears to be targeting are joined head-to-head as the spike proteins were being forced to form dimers under cryo-EM. By cross-linking the spike proteins from numerous virus particles, the researchers went on to show that SIH-5 efficiently rendered the viruses inactive.
The research team tested the peptide’s toxicity in mammalian cells and concluded that it was non-toxic. Since hamsters exposed to a high dosage of SARS-CoV-2 after receiving the peptide dose demonstrated reduced viral load and considerably less lung cell damage than hamsters exposed just to the virus, this family of peptides exhibits potential as antivirals.
With a few straightforward modifications and peptide editing, the researchers believe that this little protein made in the lab may also stop other protein-protein interactions.