Fool the new coronavirus once and it can not infect cells, new research suggests.
Scientists have developed protein fragments – called peptides – that fit well into a groove on the SARS-CoV-2 Spike protein that it normally uses to gain access to a host cell. These peptides effectively lure the virus into a handshake with a replica rather than with the actual protein on the surface of a cell that enters the virus.
Previous research has determined that the new coronavirus binds to a receptor protein on the surface of a target cell called ACE2. This receptor is located on certain types of human cells in the lung and nasal cavity, giving SARS-CoV-2 many access points to infect the body.
For this work, Ohio State University scientists designed and tested peptides that look enough like ACE2 to convince the coronavirus to bind to it, an action that blocks the virus’ ability to enter the cell.
‘Our goal is for SARS-CoV-2 to come in contact with the peptides at any time, for the virus to be activated. This is because the virus Spike protein is already bound to something it needs to use to bind to the cell, ”said Amit Sharma, co-lead author of the study and assistant professor of veterinary life sciences at the state of Ohio. “To do that, we need to go to the virus while it’s still outside the cell.”
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The Ohio State team intends to deliver, among other things, these manufactured peptides in a nasal spray or aerosol disinfectant to block circulating SARS-CoV-2 access points with an agent that prevents them from entering target cells.
“With the results we are generating with these peptides, we are well positioned to move toward product development steps,” said Ross Larue, co-author and research assistant professor of pharmaceuticals and pharmacology at Ohio State.
The study was published in the January issue of the journal Chemistry with bioconjugates.
SARS-CoV-2, like all other viruses, requires access to living cells to inflict the damage – viruses hijack cell functions to make copies of themselves and cause infection. Very rapid replication of viruses can overwhelm the host system before immune cells can produce an effective defense.
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One reason why this coronavirus is so contagious is because it binds very strongly to the ACE2 receptor, which is abundant in cells in humans and other species. The Spike protein on the SARS-CoV-2 surface that has become the most recognizable trait is also fundamental to its success in attaching to ACE2.
Recent advances in crystallizing proteins and microscopy have made it possible to create computer images of specific protein structures alone or in combination, such as when they bind together.
Sharma and his colleagues closely examined images of the SARS-CoV-2 Spike protein and ACE2 and looked closely at how their interactions take place and what compounds are needed to lock the two proteins in place. They noted a helical tail on ACE2 as the focal point of the appendix, which became the starting point for peptide design.
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“Most of the peptides we designed are based on the ribbon that comes in contact with the Spike,” said Sharma, who also has a faculty appointment in microbial infection and immunity. “We focused on creating the shortest possible peptides with the minimum of essential contacts.”
The team tested several peptides as ‘competitive inhibitors’ that could not only bind securely to SARS-CoV-2 Spike proteins, but also prevent or reduce viral replication in cell cultures. Two peptides, one with the minimum contact points and another larger, were effective in reducing SARS-CoV-2 infection in cell studies compared to controls.
Sharma described these findings as the start of a product development process that will be continued by the team of virologists and pharmaceutical chemists working together on this work.
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“We follow a multiple approach,” Sharma said. “With these peptides, we have identified the minimal contact required to deactivate the virus. We plan to focus going forward on developing aspects of this technology for therapeutic purposes.
“The goal is to neutralize the virus effectively and strongly, and now, due to the emergence of variants, we want to evaluate our technology in the light of emerging mutations.”
(Source: Ohio State – Photo by @visuals)
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