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/ Siarhei, stock.adobe.com
Pittsburg / San Francisco / Seattle – The SARS-CoV-2 pandemic has spurred the development of new drugs. These include nanobodies and protein baits, which have shown good efficacy in preclinical studies and are said to be present Science could be produced in larger quantities in less 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 pathogen, the evolution of which has evidently been shown to be beneficial. In some species, including camels 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 rather than mammalian cells), are more stable to heat, and do not necessarily have to be administered intravenously. Inhalation application would be possible and in principle also advantageous in case of respiratory diseases.
In the last few months, 2 US research groups have developed nanobodies capable of neutralizing SARS-CoV-2. Yi Shi’s team from the University of Pittsburgh produced nanobodies conventionally in lamas belonging 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. Not only was it found that the different antibodies differ in their ability to neutralize viruses. The locations of the spike protein that nanobodies recognize also vary.
According to Shi, this opens up the possibility of chemically mixing or combining different nanobodies. This would minimize the risk of viruses escaping access through mutations. According to Shi, the nanobodies last for several weeks and can be applied with a spray without any loss of effectiveness.
A team led by Peter Walter of the University of California at San Francisco is experimenting with synthetic nanobodies made with 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 binding site of the spike protein receptor and, according to the researchers, could safely prevent cell infection.
To further increase effectiveness, the researchers built a trivalent nanobody capable of neutralizing the spike protein at various points. Despite its complex structure, the antibody was chemically stable to heat. According to Walter, it could also be the basis for a drug that could prevent SARS-CoV-2 infection or relieve symptoms.
Whether this is successful and whether the treatment is safe should be demonstrated first in animal experiments and then in clinical trials.
Another way to neutralize viruses is to treat them with a synthetic protein that binds viruses and prevents them from entering the cell. A team led by Daniel-Adriano Silva of Seattle’s Neoleukin Therapeutics first designed such a protein bait on the computer and then synthesized it (Science, 2020; DOI: 10.1126 / science.abe0075).
The protein was designed to adhere to the spike protein receptor binding site. This prevents viruses from attaching to ACE receptors on pneumocytes. The divalent protein CTC-445.2, which can bind to the SARS-CoV-2 spike protein in two places, has been shown to be effective in early animal studies.
After intranasal administration, Syrian mice and hamsters were protected from infection. Here, too, it remains to be seen whether the results can be confirmed in clinical trials. © rme / aerzteblatt.de
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