Using innovative computer -based approaches, the researchers have developed protein inhibitors that block the interaction between the SARS-CoV-2 (Covid-19) virus and human cell receptor ACE2.
Called the angiotensin-converting enzyme 2, or ACE2 receptor is the protein that provides the entry point for the coronavirus to hook into and infect a wide range of human cells.
“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,” said study authors from the University of Washington in the US.
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, the study said.
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), the research team developed a series of inhibitors – optimised in their amino acid sequences for targeted binding, folding and stability.
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 said. 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 wrote.
They also address the utility of their computational design-based approach for preparing against future pandemics.