IISC scientists are developing miniproteins that can prevent COVID infection

Miniproteins can not only block the entry of viruses such as SARS-CoV-2 into our cells, but also stick virus particles together, reducing their ability to infect

Miniproteins can not only block the entry of viruses such as SARS-CoV-2 into our cells, but also stick virus particles together, reducing their ability to infect

Researchers from the Indian Institute of Science (IISc) Bangalore have designed a new class of artificial peptides or miniproteins that they believe can make viruses such as SARS-CoV-2 inactive.

According to a study published in the journal Natural chemical biologyminiproteins can not only block the entry of viruses into our cells, but also stick the virus particles together, reducing their ability to infect.

Researchers note that the protein-protein interaction is often similar to that of a lock and key.

This interaction could be thwarted by a laboratory-produced miniprotein that mimics, competes with and prevents the “key” from attaching to the “lock” or vice versa, they said.

Prevent entry

The team uses this approach to design miniproteins that can bind to and block the thorn protein on the surface of the SARS-CoV-2 virus, which helps it enter and infect human cells.

This binding was further characterized by cryo-electron microscopy (cryo-EM) and other biophysical methods.

These miniproteins are helical peptides in the shape of hairpins, each of which can fuse with another of its kind to form what is known as a dimer. Each dimer beam represents two “faces” for interaction with two target molecules.

The researchers hypothesized that the two individuals would bind to two separate target proteins, locking all four together and blocking the targets.

“But we needed proof of principle,” said Jayanta Chatterjee, an associate professor in the Department of Molecular Biophysics (MBU), IISc, and lead author of the study.

Targeting the interaction of the SARS-CoV-2 thorn protein

The team decided to test their hypothesis using one of the miniproteins called SIH-5 to target the interaction between the SARS-CoV-2 spike protein and the ACE2 protein in human cells.

The spike protein is a complex of three identical polypeptides, each of which contains a receptor-binding domain (RBD) that binds to the ACE2 receptor on the surface of the host cell, facilitating the entry of the virus into the cell.

The SIH-5 miniprotein is designed to block the binding of RBD to human ACE2.

When a SIH-5 dimer encounters an S protein, one face binds tightly to one of the three RBDs of the S protein trimmer, and the other face binds to the RBD of a different S protein.

This “cross-linking” allowed the miniprotein to block both S proteins simultaneously.

“Several monomers can block their targets. “But cross-linking S proteins blocks their action many times more effectively,” Chatterjee said.

In cryo-EM, SIH-5-targeted S proteins appear to be attached head to head, the researchers said.

“We expected to see a complex of a peak trimmer with SIH-5 peptides. But I saw a structure that was much longer, “said Somnat Duta, an assistant professor at MBU and one of the study’s co-authors.

Effective miniprotein

Dutta and others are aware that spike proteins have been forced to form dimers and accumulate in complexes with the miniprotein.

This type of aggregation can simultaneously inactivate multiple spikes of proteins of the same virus and even multiple viral particles.

The miniprotein was also found to be stable for months at room temperature without deteriorating.

Tested for toxicity

To test whether SIH-5 would be useful in preventing COVID-19 infection, the team first tested the miniprotein for toxicity in mammalian cells in the laboratory and found it to be safe.

Then, in experiments conducted in the laboratory of Raghavan Varadarajan, an MBU professor, hamsters were dosed with the miniprotein, followed by exposure to SARS-CoV-2.

These animals showed no weight loss and had a significantly reduced viral load, as well as much less cell damage in the lungs, compared to hamsters exposed to the virus alone.

The researchers noted that with minor modifications and peptide engineering, this laboratory-produced miniprotein could inhibit other protein-protein interactions.

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