Israeli-led research develops protein with potential to foil the coronavirus

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Endless lockdowns, booster shots, uncertainty about the start of the school year: Despite all the efforts by government, drug companies and scientists, the coronavirus SARS-2-CoV continues to exert its control over events in Israel and elsewhere. Now however a new international study led by Israeli researchers provides important new information about the virus that has claimed the lives of more than 4.4 million people worldwide, and proposes a new strategy for frustrating it.

Presently the primary means of dealing with COVID-19, the disease SARS-2-CoV causes, has been vaccines based on the virus’ “spike protein,” which is the means by which it attaches to human cells. For example, the Pfizer and Moderna vaccines contain mRNA (a form of the genetic code) for the spike protein, leading the cells to actually produce it. Thus our immune system learns to recognize this viral spike protein (which gives the coronavirus its “spiky” appearance), and then to resist it.

“It’s a fantastic vaccine,” said Prof. Gideon Schreiber, of the Weizmann Department of Biomolecular Sciences and head scientist of the new research. But the vaccine has become less effective for two reasons. One is that as time passes after immunization, the amount of antibodies in our bodies declines, so the booster becomes important. The second is that the virus is mutating and some of the mutations change the structure of the spike protein, or the virus’ ability to evade the immune system, he explains.

The Pfizer vaccine is especially effective in preventing the development of severe symptoms and hospitalization`; it has also been found to be highly effective in fighting infection from most of the new COVID variants. But it seems less effective at reining in the spread of the delta variant.

Prof. Gideon SchreiberWeizmann Institute of Science

This is the background against which a team from Israel’s Weizmann Institute of Science, working with people at the Institut Pasteur in France and the U.S. National Institutes of Health, set out to develop a way to block the virus from accessing our cells. They focused on the receptor to which the virus attaches on the surface membrane of our cells. That receptor is called ACE2, and it is there that the spike protection binds.

What they did is to create a protein that binds to the human receptor more efficiently than the spike protein does. If the receptors on our cells are “occupied,” the virus can’t bind.

“Most antibody developers developed something that bonds to the virus itself,” explained Schreiber. “But because the viruses undergo changes, we wanted to develop something that wouldn’t be affected by those changes.”

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Evolution in a test tube

Experiments testing the efficacy of the molecule in animals were published last week in the journal Nature Microbiology. The researchers led by Jiri Zahradnik of the Weizmann Institute isolated the specific part of the spike protein that binds to ACE2 and took it through a process of “in vitro evolution.”

This technique won its inventor Frances Hamilton Arnold, together with George Smith and Gregory Winter, the Nobel Prize three years ago. It mimics the process of natural selection, but at a much faster pace.

“We take a segment of DNA that codes for the protein and replicate it in vitro,” explained Schreiber. “You can play with the conditions in which this replication is being done. That’s what we did, and we got billions of mutations of the original protein. In the next stage, we marked the ACE2 and bound it with the pieces of protein that were produced.” They then tested each coupled ACE2-protein pair for the strength of the bond; and each time, chose the most strongly bound ones.

Healthcare worker applies anti-COVID-19 vaccine at a drive-in vaccination center in Berlin, Germany, July 2021AXEL SCHMIDT / REUTERS

Thus the researchers developed a protein that binds to ACE2 1,000 times more intensely than coronavirus spike protein, crucially — without impairing ACE2’s natural activity.

To create a potential medicine from this new protein, an inhaler was developed in cooperation with Prof. Yinon Rudich of the Weizmann Institute’s Earth and Planetary Science department. The result was tested at the NIH on hamsters, whose ACE2 receptors are similar to humans.

The virus isn’t fatal to hamsters but causes them to lose a lot of weight, especially in males, Schreiber says. The experiment found that hamsters who didn’t receive the treatment lost three times their weight, compared with hamsters who did receive the treatment, even when only small amounts of the protein were delivered. It significantly reduced the rodents’ symptoms and the severity of the illness whether administered before infection or after infection. The NIH is expected to carry out additional research shortly and to start pre-clinical monkey trials.

The researchers expect that the new molecule will be used mainly on humans with the strong potential for developing a severe case of COVID.

In the course of their experiment, the researchers made another discovery.

“We didn’t anticipate it at all, but we looked at the mutations that were created at the beginning of the process, and they were the same mutations that the virus [evolved] toward – the British [alpha] strain, the South African [beta] and the Brazilian [gamma],” Schreiber recounted. Which means: the evolution in the lab they carried out, to create a strong bind, simulated the natural evolution that the virus underwent during the first year of the pandemic in the real world.

This, the researchers say, indicates linkage between virulence and the strength of binding to the ACE2 receptor.

Dr. Moshe Dessau, the director of the structural biology infectious disease lab at the Azrieli medical school at Bar-Ilan University, who was not involved in the study, qualified that he expects it will take a long time before the study might lead to an actual drug. “But it’s an interesting strategy. Beyond that, the research provides us with information about the virus that we hadn’t had up to now,” he said. “There are a lot of articles on COVID-19, but few of them provide, as this one does, a biophysical, numerical and quantitative expression to the link of the virus to the receptor, which is a critical point in the whole process of infection.”