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“Two-Faced” Miniproteins Protect Against Infection of Cells by SARS-CoV-2
Synthetic miniproteins that disable the entry of SARS-CoV-2 viruses into human cells have been developed, offering a potential alternative for enhanced protection from COVID-19.

The constant waves of novel strains of SARS-CoV-2 virus have weakened the effectiveness of the COVID-19 vaccines. However, a new approach to blocking the entry of SARS-CoV-2 into cells has been discovered by researchers at the Indian Institute of Science (IISc), opening avenues to the potential use of alternative technologies to confer additional protection against the virus.

The researchers reported their development of a newly-formed, unique class of proteomimetics – artificial peptides that draw inspiration from pre-existing proteins, having been modified to improve on functions like heat stability and robustness. This class of proteomimetics, also known as SIH-5 miniproteins, can impede the entry of the virus into living cells, as well as cluster the virus particles together, reducing their infection capabilities, and can be stored at room temperature for extended periods without degradation.

As inter-protein interactions allow different proteins to bind to each other, the researchers sought to design a molecule that would bind to the spike proteins on the surface of the SARS-CoV-2 virus, such that they would be unable to use their spike proteins to bind with receptors for entry into cells. After designing the molecule, its mechanism of action and properties were further studied using cryo-electron microscopy (cryo-EM) and other analytical techniques.

Their efforts produced thermostable synthetic proteins with hairpin-shaped, helical peptides that pair up with each other, resulting in a structure known as a dimer. Each miniprotein in the dimer can form interactions with two separate proteins. The researchers hypothesised that each dimer could form interactions with two other different proteins, forming a complex that would enmesh the spike protein to render it useless.

The spike protein comprises three polypeptides of the same kind (trimer). Each polypeptide contains a Receptor Binding Domain (RBD) that binds to the ACE2 receptor on the host cell surface, triggering the cell to facilitate entry of the virus via endocytosis.

In their experiments, the researchers confirmed that their designed SIH-5 miniproteins did indeed manage to block the binding of the spike protein’s RBD to a human ACE2 receptor through a novel mechanism. Once part of the miniprotein interacted with one of the RBDs on the spike protein, favourable interactions formed, binding both compounds together. Since the miniprotein has multiple binding sites, it can further bind to another RBD on another spike protein, allowing for “cross-linking” to block multiple spike proteins with a single miniprotein. “Cross-linking of S proteins blocks their action many times more effectively. This is called the avidity effect,” says Jayanta Chatterjee, Associate Professor from the Molecular Biophysics Unit (MBU) at IISc.

The miniproteins forced the spike proteins to form dimers and enmeshed them into complexes, allowing for the clustering of multiple spike proteins from different viruses, and by extension multiple virus particles, proving its high efficacy in inactivating viruses. “I have worked with antibodies raised against the spike protein before and observed them under a cryo-EM. But they never created dimers of the spikes,” says Somnath Dutta, Assistant Professor from the MBU at IISc and one of the corresponding authors.

To explore the usage of these proteins as protection from the infection of human cells by COVID-19, researchers, under the guidance of Raghavan Varadarajan, Professor from the MBU at IISc, performed tests where the hamsters were administered miniproteins before they were exposed to SARS-CoV-2 viruses. The findings from this experiment showed that the animals treated with the miniproteins had a large reduction in their viral load, did not suffer from weight loss, and had reduced lung cell damage compared to the control group.

Thus, the researchers are optimistic that with further research and modifications, their miniprotein approach may be used to inhibit inter-protein interactions and reduce infections by other different strains of viruses.

Source: Khatri et al. (2022). A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.Nature Chemical Biology.

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