Chemists at the Massachusetts Institute of Technology (MIT) have chemically synthesized a new peptide (a short protein fragment) that can bind to part of SARS-CoV-2’s spike protein, a key protein responsible for getting the virus into mammalian cells, potentially disarming it.
Zhang et al designed a peptide that can bind to part of SARS-CoV-2’s spike protein. Image credit: Christine Daniloff, MIT.
“We have a lead compound that we really want to explore, because it does, in fact, interact with a viral protein in the way that we predicted it to interact, so it has a chance of inhibiting viral entry into a host cell,” said senior author Dr. Brad Pentelute, a researcher in the Department of Chemistry at MIT.
Coronaviruses, including SARS-CoV-2, have many protein spikes protruding from their viral envelope.
A specific region of SARS-CoV-2’s 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.
In hopes of developing drugs that could block viral entry, Dr. Pentelute and colleagues performed computational simulations of the interactions between the ACE2 receptor and the receptor binding domain of SARS-CoV-2’s 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.
“This kind of simulation can give us views of how atoms and biomolecules interact with each other, and which parts are essential for this interaction,” said first author Dr. Genwei Zhang, a postdoctoral researcher in the Department of Chemistry at MIT.
“Molecular dynamics helps us narrow down particular regions that we want to focus on to develop therapeutics.”
The scientists 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 benchtop flow-based peptide synthesis machine can form linkages between amino acids, the buildings 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 using equipment at MIT’s Biophysical Instrumentation Facility that can measure how strongly two molecules bind together.
They found that the longer peptide showed strong binding to the receptor binding domain of SARS-CoV-2’s spike protein, while the shorter one showed negligible binding.
The team is now developing about 100 different variants of the peptide in hopes of increasing its binding strength and making it more stable in the body.
“We have confidence that we know exactly where this molecule is interacting, and we can use that information to further guide refinement, so that we can hopefully get a higher affinity and more potency to block viral entry in cells,” Dr. Pentelute said.
In the meantime, the researchers have already sent their original 23-amino acid peptide to a research lab at the Icahn School of Medicine at Mount Sinai for testing in human cells and potentially in animal models of COVID-19 infection.
The team’s paper was posted on the bioRxiv.org preprint server on March 20, 2020.
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G. Zhang et al. 2020. The first-in-class peptide binder to the SARS-CoV-2 spike protein. bioRxiv, doi: 10.1101/2020.03.19.999318
This article is based on text provided by the Massachusetts Institute of Technology.
