In a new study, researchers have designed a drug candidate that they believe may block coronaviruses’ ability to enter human cells.
The potential drug is a short protein fragment, or peptide, that mimics a protein found on the surface of human cells.
The researchers have shown that their new peptide can bind to the viral protein that coronaviruses use to enter human cells, potentially disarming it.
The research was conducted by a team of MIT chemists.
The team began working on this project in early March, after the Cryo-EM structure of the coronavirus spike protein, along with the human cell receptor that it binds to, was published by a research group in China.
Coronaviruses, including SARS-CoV-2, which is causing the current COVID-19 outbreak, have many protein spikes protruding from their viral envelope.
Studies of SARS-CoV-2 have also shown that a specific region of the spike protein, known as the receptor-binding domain, binds to a receptor called angiotensin-converting enzyme 2 (ACE2).
This receptor is found on the surface of many human cells, including those in the lungs. The ACE2 receptor is also the entry point used by the coronavirus that caused the 2002-03 SARS outbreak.
In hopes of developing drugs that could block viral entry, the team performed computational simulations of the interactions between the ACE2 receptor and the receptor-binding domain of the coronavirus spike protein.
These simulations revealed the location where the receptor-binding domain attaches to the ACE2 receptor—a stretch of the ACE2 protein that forms a structure called an alpha helix.
The MIT team then used peptide synthesis technology to rapidly generate a 23-amino acid peptide with the same sequence as the alpha helix of the ACE2 receptor.
Their peptide synthesis machine can form linkages between amino acids, the building blocks of proteins, in about 37 seconds, and it takes less than an hour to generate complete peptide molecules containing up to 50 amino acids.
They also synthesized a shorter sequence of only 12 amino acids found in the alpha helix, and then tested both of the peptides.
They found that the longer peptide showed strong binding to the receptor-binding domain of the COVID-19 spike protein, while the shorter one showed negligible binding.
They are now developing about 100 different variants of the peptide in hopes of increasing its binding strength and making it more stable in the body.
In the meantime, the researchers have already sent their original 23-amino acid peptide to a research lab at Mount Sinai for testing in human cells and potentially in animal models of COVID-19 infection.
While dozens of research groups around the world are using a variety of approaches to seek new treatments for COVID-19, this team is one of a few currently working on peptide drugs for this purpose.
One advantage of such drugs is that they are relatively easy to manufacture in large quantities. They also have a larger surface area than small-molecule drugs.
One drawback of peptide drugs is that they typically can’t be taken orally, so they would have to be either administered intravenously or injected under the skin.
They would also need to be modified so that they can stay in the bloodstream long enough to be effective.
One author of the study is Brad Pentelute, an MIT associate professor of chemistry.
The study is published in BioRxiv.
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