Using innovative computer-based approaches, researchers have developed protein inhibitors that block the interaction between the SARS-CoV-2 virus and human cell receptor ACE2. In cell culture, the most potent of these inhibitors could neutralize virus infection, paving the way for their use in therapies that could be delivered more easily than antibodies. SARS-CoV-2 infection generally begins in the nasal cavity. The monoclonal antibodies in development as treatments for COVID-19 are not ideal for intranasal delivery, however, as antibodies are large and often not extremely stable. Small proteins that bind tightly to the SARS-CoV-2 spike and block the interaction with the human cellular receptor ACE2 may allow direct delivery through intranasal administration. Previous work in rodents has shown that intranasal delivery of small proteins designed to bind tightly to an influenza protein could provide protection against infection. Here, using novel approaches to identify new, higher-affinity binding modes with the SARS-CoV-2 spike’s receptor binding domain (RBD), Longxing Cao, David Baker and colleagues developed a series of inhibitors – optimized in their amino acid sequences for targeted binding, folding and stability – that bound to distinct regions of the RBD surface surrounding the ACE2 binding site. When they evaluated their inhibitors in cell culture, several bound with particularly high affinities to SARS-CoV-2 and two neutralized the virus, preventing infection. The small proteins were stable after 14 days at room temperature, addressing concerns associated with cold storage needs required for some antibodies and vaccine candidates. These “minibinders” provide starting points for SARS-CoV-2 therapeutics, the authors say. After further development, they could be used in a gel for nasal application, or for direct delivery into the respiratory system by nebulization. “We will be exploring alternative routes of delivery in the months ahead as we seek to translate the high potency neutralizing proteins into SARS-CoV-2 therapeutics and prophylactics,” they write. They also address the utility of their computational design-based approach for preparing against future pandemics.
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