
The potential drug is a short protein, or peptide, like a protein found on the surface of human cells. The researchers have shown that their new peptide can bind to the protein coronavirus uses to invade human cells to inhibit it.
"We have a compound that we really want to discover because in fact it interacts with the viral protein in the way that we predict it will interact. So it has the opportunity to inhibit the entry of the virus into the host cell, ”said Brad Pentelute, associate professor of chemistry at MIT, who led the research.
The team has now sent peptide samples to collaborators planning to perform tests in human cells.
Pentelute’s lab started working on the project earlier in March 2020, after a team in China announced the spiny protein structure of a new strain of coronavirus along with a cell receptor. which it binds when viewed under a cold electron microscope (cryo-electron microscopy).
Studies on SARS-CoV-2 indicate that a specific region of the protein spikes, called a receptor bound domain, binds to a receptor called the angiotensin 2 conversion enzyme (ACE2). This receptor is found on the surface of many human cells, including in the lungs. The ACE2 receptor is also the entry point for the coronavirus that caused the SARS 2002-03 outbreak.
Hoping to develop drugs that could prevent the virus from invading, Genwei Zhang, a postdoctoral fellow in the Pentelute lab, performed computational simulations of the interaction of ACE2 receptor. and the domain associated with the coronavirus protein receptor. These simulations revealed the location where the receptor binding domain binds to the ACE2 receptor, a protein fragment of the ACE2 protein that forms a structure called the alpha helix.
This type of simulation can give us a better idea of how atoms and biomolecules interact with each other, and which parts are essential for this interaction, Zhang Zhang said.
The MIT team then used the peptide synthesis technology that the Pentelute lab had developed earlier, to quickly create a 23 amino acid peptide with the same sequence as the ACE2 receptor helix sequence. . The peptide synthesizer can form bonds between amino acids and protein blocks in about 37 seconds and takes less than an hour to create complete peptide molecules containing up to 50 amino acids.
They also synthesized a shorter chain of only 12 amino acids found in the alpha helix, and then tested both peptides using equipment at MIT that could measure how strong the two molecules were. The researchers found that longer peptides showed a strong binding to the receptor binding domain of the Covid-19 protein, while shorter ones showed no significant binding.
Although MIT has scaled down research since mid-March, the Pentelute lab has been specifically licensed to allow a small group of researchers to continue working on the project. They are currently developing around 100 different variants of peptides in the hope of increasing bond strength and making it more stable.
“We are confident that we know exactly where this molecule is interacting and we can use that information to further guide refining, so we can hope for a higher relationship. and more potential to prevent the entry of viruses into cells, ”Pentelute said.
While dozens of research groups around the world are using different approaches to find new treatments for Covid-19, Pentelute believes the lab is one of the few places where research is currently available. are using peptides for this purpose. One advantage of such drugs is that they are relatively easy to produce in large quantities. They also have a larger surface area than small molecule drugs.
Peptides are a larger molecule, so they can actually cling to coronavirus and inhibit cell entry, whereas if you use a small molecule, it’s difficult to block the entire area of The virus is under control. Antibodies also have a large surface area, so they can also be helpful.
However, a limitation of peptides is that it cannot be used orally but must be injected into a vein or under the skin. The medication also needs adjustments so it can stay in the bloodstream long enough to be effective.
“I have a hard time predicting how long it will take to test something in a patient, but my goal is within a few weeks. If it becomes more difficult, it could take several months, ”Pentelute emphasized.