Fred Hutch Scientists Maps the Structure of Potent Coronavirus Antibody

Fred Hutch Scientists Maps the Structure of Potent Coronavirus Antibody

Neutralization of SARS-CoV-2 by the immune proteins displayed using computer-generated images.
A potent antibody that is taken from a COVID-19 survivor is found to interfere with distinctive spikes on the surface of the coronavirus, which is a key feature of the virus and results in the breaking of a critical piece of those distinctive spikes in the process. This process was reported by scientists at the Fred Hutchinson Cancer Research Center, Seattle.

The Fred Hutch team isolated a tiny Y-shaped antibody-protein that happens to be a premier weapon of the body against pathogens, including viruses. The antibody is collected from an early day’s pandemic patient in Washington state by the team.

The team of researchers is lead by Drs. Leo Stamatatos, Andrew McGuire, and Marie Pancera. The team reported that a patient naturally generates dozens of different types of antibodies, and among those antibodies, this particular antibody–dubbed CV30– was found to be 530 times more potent compared to its competitors.

Map of the Coronavirus Antibody Structure

Pancera, a structural biologist in the university, and Dr. Nicholas Hurlburt, a postdoctoral fellow under her, successfully mapped the molecular structure of CV30 with

the help of tools derived from high-energy physics. The results of the study were published yesterday in the journal Nature Communications.

The results of the study is a set of 3-D images generated in the computer that might seem to be a mass of unruly noodles to the untrained eye. The result images display precise shapes of proteins with surface structures of antibodies that are critical, the spikes of the coronavirus, and the binding site of the spike on human cells. The model depicted how the structures fit in together like pieces of a 3D puzzle.

Pancera said that the study shows how two mechanisms of the antibody neutralize the virus. One of the mechanisms is that the target site of the virus on human cells is overlapped by the antibody and the other mechanism is that shedding or dissociation of the spike parts from the other spikes is induced.

On the tips of each of its floppy, Y-shaped arms, there is a spot, which is located on the surface of the complex antibody structure. A spot on the spike of the coronavirus, which is the site working as a grappling hook used for grabbing onto a docking site on human cells, is the place where the infinitesimally small molecule patch is stretched neatly.

ACE2 is a receptor protein that is present on the human lung tissue cell surface and in the surface of blood vessel cells. The target of those spike hooks of the virus is the ACE2 receptors. But the hooks cannot dock easily with the ACE2 receptor if CV30 antibodies cover those hooks. The ability of the virus to infect cells is now blunt with the CV30 antibodies.

Apart from jamming the route of the coronavirus spike, the antibody also shears off a section of the spike of the virus, known as S1. McGuire, a researcher in Hutch, and his team showed in an experiment that in the presence of CV30 antibody, there was a reduction in the binding of the antibody over time, which suggested the shedding off of the S1 section on the spike surface.

The coronavirus enters cells with major help from the S1 protein. Research indicates that after the initial contact of the spike with the ACE2 receptor, the virus fuses with the captured cell surface with the help of the S1 protein as it swings like a gate and slips inside. once the virus enters the cells, it hijacks the gene components and the machinery that makes proteins and makes multiple copies of itself that target and infect other cells

It is difficult to comprehend the antibodies due to its incredibly smaller size. The proteins are small enough to swarm around a virus, like mosquitos, while the structure of the virus itself is so minute that it can be seen only through the most powerful of microscopes. The tips of the antibody proteins which is being studied by the Fred Hutch team are measured in nanometers- billionths of a meter.

Despite the minute size, with the help of the right tools, structural biologists can now build accurate images in 3D of these proteins, deduce the interactions between them to fit in like pieces of a puzzle, and even the interactions can be animated.

The 3D images of the antibodies are taken from blood samples present in a COVID-19 survivor when the pandemic was at its initial stage. These antibodies were found to neutralize the coronavirus efficiently.

Dr. Nicholas Hurlburt, who helped to develop the antibody 3D images, narrated in a small video the mechanism and the interaction between the antibodies and the notorious spikes of the coronavirus.

The model of these nanoscale structures is built using X-ray crystallography. Shapes of proteins are determined by structural biologists by illuminating the samples with extremely powerful X-rays. The samples are frozen and kept in a crystallized form. Synchrotron light source is a gigantic instrument that radiates the most powerful X-rays. This extremely powerful radiating X-ray machine was a result of atom-smashing experiments performed back in the 1930s, a stream of electrons is accelerated around a circular track at close to the speed of light with the help of a ring of massively powerful magnets called the synchrotron.

In this study,  a synchrotron at Argonne National Laboratory, Chicago, was used, which is the Advanced Photon Source. The laboratory is on a site of 80-acres and has a 1,200 feet diameter ring, and is run by the University of Chicago and the U.S. Department of Energy.

With the whizzing of the electron around the synchrotron ring, enormously powerful X-rays are radiated, which is far brighter than the sun, but these rays are delivered in beam flashes smaller than a pinpoint.

In order to illuminate frozen crystals of protein, structural biologists from around the world come for these brilliant X-ray beamlines. As the beamlines pass through the molecules, the structure of the molecules is revealed. The data readouts generated from synchrotron experiments can be translated into images of proteins with the help of powerful computers that are later completed by structural biologists.

For structural biologists studying a growing family of antibodies with potent neutralizing capabilities against coronavirus, this study by the Fred Hutch team will help to build on and progress further. The goal of most vaccines against coronavirus will be to stimulate and train the immune system to produces neutralizing antibodies with similar properties that would recognize the virus to be a foreign entity, and before the COVID-19 infection takes over, the immune system should be able to take hold of it.

As an experimental approach, neutralizing antibodies taken from the blood of patients who have recovered from COVID-19 may also be infused into an infected individual – this approach is known as convalescent plasma therapy. A variety of antibodies with varying potency might be present in the donated plasma. This approach was once thought to be promising, but its effectiveness has been questioned in recent studies.

However, combinations of potent antibodies with the ability to neutralize infection are experimented by pharmaceutical companies. These antibodies should be grown in laboratories easily. As a therapeutic, the monoclonal antibody cocktail can be infused in the blood of COVID-19 patients or can be given as prophylactic drugs after its production on the industrial scale. President Donald Trump, after coming down with COVID-19, received monoclonal antibody treatment generated in Regeneron, which is a biotech company. The monoclonal drug was in the stage of its clinical trial.

The research team of the Fred Hutch hopes that the discovered CV30 protein can be useful to prevent or treat COVID-19. In order to find the effectiveness of the discovered antibody along with other antibodies studied by the team, it should be tested preclinically first and then move to human trials.

Pancera said that it is too early to tell how good the discovered antibody might be.

This study was sponsored by donations made to the COVID-19 Research Fund, Fred Hutch.

Source

Fred Hutch Scientists Maps the Structure of Potent Coronavirus Antibody, Map of the Coronavirus Antibody Structure.