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Drug research: nanobodies and protein baits are supposed to stop SARS-CoV-2

/ Siarhei, stock.adobe.com

Pittsburg / San Francisco / Seattle - The SARS-CoV-2 pandemic has stimulated the development of novel drugs. These include nanobodies and protein baits, which have shown good efficacy in preclinical studies and are reported to be in Science could be produced in larger quantities in a shorter time. However, it is likely to be too early for clinical use.

The immune system of most mammals, including humans, produces antibodies with two binding sites (domains) for the pathogens, which evolution has evidently proven to be beneficial. In some species, including camel animals and cartilaginous fish, the immune system also produces antibodies with only one binding site.

These single domain antibodies or nanobodies are interesting for drug research because they are easier to produce (in bacteria instead of mammalian cells), are more heat stable and do not necessarily have to be administered intravenously. Inhalative application would be possible and in principle also advantageous in the case of respiratory diseases.

In the last few months, 2 research groups from the USA have developed nanobodies that can neutralize SARS-CoV-2. Yi Shi's team from the University of Pittsburgh produced the nanobodies in a conventional way in llamas, which belong to the camel family (Science, 2020; DOI: 10.1126 / science.abe4747).

The researchers injected the animals with short proteins that contained the binding site of the spike protein. Two months later, they were able to isolate the nanobodies from the animals' blood.

These nanobodies were then tested in laboratory experiments for their ability to prevent SARS-CoV-2 from infecting cells. It turned out not only that the different antibodies differ in their ability to neutralize the viruses. The locations of the spike protein that the nanobodies recognize also vary.

According to Shi, this opens up the possibility of mixing or chemically combining different nanobodies. This would minimize the risk that the viruses could evade access through mutations. According to Shi, the nanobodies have a shelf life of several weeks and can be applied with a spray without any loss of effectiveness.

A team led by Peter Walter from the University of California in San Francisco is experimenting with synthetic nanobodies produced in yeast (Science, 2020; DOI: 10.1126 / science.abe3255).

In a screening of more than 2 billion possible sequences, a nanobody was found that recognizes the receptor binding site of the spike protein and, according to the researchers, could safely prevent infection of the cells.

To further increase the effectiveness, the researchers constructed a trivalent nanobody that can neutralize the spike protein at various points. Despite its complex structure, the antibody was chemically heat-stable. According to Walter, it could also be the basis for a drug that could prevent infection with SARS-CoV-2 or reduce symptoms.

Whether this succeeds and whether the treatment is safe would first have to be shown in animal experiments and then in clinical studies.

Another way to neutralize the virus is to treat it with a synthetic protein that binds the virus and prevents it from entering the cell. A team led by Daniel-Adriano Silva from Neoleukin Therapeutics in Seattle first designed such a decoy protein on the computer and then synthesized it (Science, 2020; DOI: 10.1126 / science.abe0075).

The protein was designed to adhere to the receptor binding site of the spike protein. This prevents the viruses from docking with the ACE receptors on the pneumocytes. The bivalent protein CTC-445.2, which can attach itself to the spike protein of SARS-CoV-2 in two places, has proven to be effective in first animal studies.

After intranasal administration, mice and Syrian hamsters were protected from infection. Here, too, it remains to be seen whether the results can be confirmed in clinical studies. © rme / aerzteblatt.de