Researchers have announced the design of a new class of synthetic peptides that can not only block the entry of the SARS-CoV-2 virus into cells, (virus particles) together, reducing their ability to infect. This new approach provides an alternative mechanism for neutralizing viruses such as SARS-CoV-2 and holds promise for a new class of peptides as antivirals. The rapid emergence of new strains of the SARS-CoV-2 virus has reduced the protection offered by COVID-19 vaccines and requires new approaches to prevent infection with the virus.
It is known that the protein-protein interaction is often similar to the lock-key interaction. This interaction can be hindered by a synthetic peptide that mimics the key, competing with it and preventing it from binding to the ‘lock’, or vice versa. Scientists from the Indian Institute of Science (IISc), in collaboration with researchers from the CSIR-Institute of Microbial Technology, used this approach to design peptides that can bind to and block the spike protein on the surface of the SARS-CoV-2 virus. . This binding was further extensively characterized by cryo-electron microscopy (cryo-EM) and other biophysical methods.
The research was supported under the COVID-19 IRPHA call by the SERB Science and Engineering Research Board (SERB), a statutory body of the Department of Science and Technology (DST). The designed peptides are helical, hairpin-shaped, each capable of pairing. with another of its kind, forming what is known as a dimer. Each dimeric “bundle” represents two “faces” for interaction with two target molecules. In a study published in Nature Chemical Biology, the researchers hypothesized that the two faces would bind to two separate target proteins, locking all four in a complex and blocking the targets’ activity. The team decided to test their hypothesis by using a peptide called SIH-5 to target the interaction between the Spike (S) protein of SARS-CoV-2 and the ACE2 protein, the SARS-CoV-2 receptor in human cells.
Protein S is a trimer – a complex of three identical polypeptides. Each polypeptide contains a receptor binding domain (RBD) that binds to the ACE2 receptor on the surface of the host cell. This interaction facilitates the entry of the virus into the cell.The SIH-5 peptide was designed to block the binding of the RBD to human ACE2. When the SIH-5 dimer encountered protein S, one of its faces tightly bound to one of the three RBDs on the protein S trimer, and the other side bound to an RBD from another protein S. This “cross-linking” allowed SIH-5 to block both S proteins at the same time. By cryo-EM, SIH-5-targeted S proteins appeared to be attached head-to-head and spike proteins were forced to form dimers. Subsequently, the researchers showed that SIH-5 effectively inactivated viruses by cross-linking spike proteins from different viral particles.
A team comprising B Khatri, I Pramanick, SK Malladi, RS Rajmani, P Ghosh, N Sengupta, R Varadarajan, S Dutta and J Chatterjee from the Indian Institute of Science (IISc), R Rahisuddin, S Kumar, N Kumar, S Kumaran and RP Ringe of the CSIR-Institute of Microbial Technology tested the peptide for toxicity in mammalian cells in the laboratory and found it to be safe. When hamsters were given the peptide and then exposed to a high dose of SARS-CoV-2, they showed reduced viral loads as well as much less cell damage in the lungs compared to hamsters exposed to the virus alone, demonstrating the promise of this class of peptides as an antiviral. The researchers believe that with minor modifications and peptide engineering, this lab-made miniprotein could also inhibit other protein-protein interactions.
