We have developed a novel therapeutic for SARS-CoV-2 that relies on nanobodies – antibody fragments from alpacas and llamas. Combining protein engineering, structural biology, and virology, we found that multi-component molecules binding the virus on two surfaces lead to robust neutralization of wildtype virus and newly emerging variants. Unlike most antibodies, our camelid nanobodies induced the premature activation of the fusion activity, rather than just preventing binding.

Our team took advantage of a peculiar type of antibodies that are produced by all camelids in response to immunizations, and which have a less complex structure than normal antibodies. We could extract the information for the smallest necessary fragment sufficient to bind to the spike protein of SARS-CoV-2 with high specificity, and test which of them interfere with infection. Using structural and functional data, we synergistically combined the best candidates into multi-component molecules that efficiently neutralized viruses, prevented the emergence of escape variants, and successfully inactivated all emerging variants. The excellent potency is based on the low chance to develop escape mutations against multiple surfaces at the same time, and on the unusual mode of action, which led to the premature destruction of the viral fusion protein. The developed molecules counteract infection in animal models, are efficiently produced in yeast, and are suitable for application by inhalators.

Tags: Nanobodies, Camelid Nanobodies, SARS-CoV-2 Virus, Alpaca, Llama

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