Nanobodies have been developed that can prevent the SARS-CoV-2 coronavirus from entering human cells – even if the virus mutates, several research teams have announced.
Researchers at Karolinska Institutet, Sweden, working with teams in Germany and the USA, say a combined nanobody demonstrated a particularly good effect and has the potential to be developed into a treatment for the virus.
Writing in Science, they describe generating the nanobodies by vaccinating alpacas and llamas with the spike protein of the coronavirus and selecting the best binders.
A blood sample was taken from the animals, from which the researchers extracted the genetic information of produced antibodies before extracting those that recognised the coronavirus’ spike protein. Four molecules were effective against the pathogen in cell cultures.
Lead author Dr Paul-Albert König, head of the Core Facility Nanobodies at the Medical Faculty of the University of Bonn, Germany, said: “Using X-ray structures and electron microscopy analyses, we were furthermore able to show how they interact with the spike protein of the virus.”
The spike protein acts like a Velcro fastener with which the pathogen attaches to the attacked cell. When the “Velcro” changes its structure, it discards the component that is important for attachment and mediates fusion of the virus envelope with the cell.
“Nanobodies also appear to trigger this structural change before the virus encounters its target cell – an unexpected and novel mode of action,” said Dr König. “The change is likely to be irreversible; the virus is therefore no longer able to bind to host cells and infect them.”
Corresponding author Dr Martin Hällberg, researcher at the Department of Cell and Molecular Biology at Karolinska Institutet, said: “What is uniquely special here is that we have stitched together nanobodies that bind to two different places on the spike protein of the virus.
“This combination variant binds better than individual nanobodies and is exceptionally effective in blocking the virus’ ability to spread between human cells in cell culture.”
The combined nano-antibodies were also found to work when tested on a quickly mutating virus variant.
“This means that the risk is very small that the virus would become resistant to these combined nanobodies,” added Dr Hällberg.
He said the llama nanobody binds directly over the surface where the virus binds the host cell receptor ACE2, and the nanobody also shares a large majority of the amino acids critical for binding with ACE2.
“What this means is that the virus will have an extremely difficult time mutating extensively on that surface and at the same time being able to bind ACE2,” he said.
“A variant where this llama antibody is linked to one of the antibodies from alpaca was a fox trap that the virus never managed to get out of in our experiments.”
The researchers hope these nanobodies could be developed into a drug treatment as a complement to a vaccination against COVID-19.
Dioscure Therapeutics, a spin-off company from the University of Bonn, is to conduct further testing of the nanobodies in clinical trials. The researchers at Karolinska Institutet will make attempts to improve the binding further by changing individual building blocks in the nanobodies.
König P-A, Das H, Liu H et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science 12 January 2021; doi: 10.1126/science.abe6230.
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