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Aragonese researchers improve them to neutralize the infection. The small 'nanobodies' of camelids could be a future inhalable drug.
This story begins with a llama, that Andean camelid with its highly prized wool. But what interests science now is not their wool, but their antibodies. Because they are smaller - that's why they are called 'nanobodies' - and it is easier to work with them to, in this case, improve them so that they can become drugs that make coronavirus infection more difficult, blocking its entry into human cells.
On Ramón Hurtado-Guerrero's computer there is already a battery of computationally designed nanoantibodies ('nanobodies') that, once purified and characterized, will be tested in the laboratory. First in cells and then in mice.
The flame works here as a factory of antibodies against covid-19, "just like us who, if we are exposed to the virus, generate antibodies," says Hurtado, Araid researcher at the Institute of Biocomputing and Physics of Complex Systems of the University from Zaragoza. But llama 'nanobodies' are so appreciated because, in addition to being small, "they are more soluble and easier to express, which means that, in a simple way, large quantities, milligrams or grams, can be obtained."
Master key sabotage
SARS-CoV2 has a master key to enter our cells. It is in the 'spike' protein, those spicules that protrude from the coronavirus. Scientists already know which part of the spike fits perfectly with a hole in our cells that would act as a lock. The RBD domain of the 'spike' of the coronavirus fits like a glove of the human receptor protein of the virus: ACE2. "RBD binds to ACE2 and the cell door opens, thus the virus penetrates human cells," explains Hurtado. "What we want is to prevent this binding and, therefore, prevent the virus from infecting."
That is the function of the nanoantibodies that, through protein engineering, they are designing. Let them be the ones who fit into that coronavirus key to block it and prevent the progression of the disease. I can't help but think of an angry bull.
A beastly competition
The experiment begins by injecting the area of SARS-CoV2 of interest into the flames: the RBD domain of the 'spike' protein, so that "these animals generate antibodies against this specific protein."
At this time, "competition is brutal" and groups from all over the world have the same objectives, but very different means, "so the richest countries beat us in almost everything," he considers. In the last three months, nanoantibodies against RDB have already appeared as a result of research in the United States and the United Kingdom and a third is about to appear. Therefore, the project by Hurtado, Julián Pardo and Eva Gálvez, financed by the Government of Aragon, has taken these nanoantibodies already described as a starting point with the aim of improving them. "Computationally, in collaboration with Juan Fernández-Recio, from the Barcelona Supercomputing Center, we have designed 19 improved mutants of these antibodies."
They have already cloned them in an appropriate vector for their expression: the Escherichia coli bacteria, "a very simple and very cheap system." When they are ready and purified, they will study, using physical-chemical techniques, which ones bind best to RBD to move on to studies in mammalian cells. The team of Julián Pardo, Araid researcher at the Aragón Health Research Institute, and Eva Gálvez, from the Carbochemistry Institute (CSIC), will evaluate which ones inhibit infection the most. After this 'casting' of nanoantibodies, only the best will go to mouse models. These preclinical trials, in animals, could be the prelude to a drug against covid-19 made with antibodies that neutralize the infection.
And if a llama was at the beginning of this story, we find it again at the end, since, thanks to its simple structure, llama antibodies can be nebulized and administered through an inhaler. Thus, future neutralizing antibody therapy could be applied directly to the patient's airways. Although he is not part of this project, Hurtado is already planning to make liposomes with antibodies on the outside to nebulize and for the treatment to enter, in this case into the mouse, through the nose.
