A new protein-based antiviral nasal spray developed by researchers at Northwestern University, Washington University and Washington University in St. Louis is being developed into Phase I human clinical trials for treat COVID-19.
Computer-engineered and refined in the lab, new protein therapies thwarted infection by interfering with the virus’s ability to enter cells. The superior protein neutralized the virus with similar or greater potency than antibody treatments with U.S. Food and Drug Administration (FDA) Emergency Use Authorization status. Notably, the top protein also neutralized all tested SARS-CoV-2 variants, which many clinical antibodies failed to do.
When the researchers gave the treatment to mice in the form of a nasal spray, they found that the best of these antiviral proteins reduced symptoms of infection — or even prevented infection altogether.
The results were published yesterday (April 12) in the journal Science translational medicine.
This work was led by Michael Jewett of Northwestern; David Baker and David Veesler of the University of Washington School of Medicine; and Michael S. Diamond at WashU.
To get started, the team first used supercomputers to design proteins that could stick to vulnerable sites on the surface of the novel coronavirus, targeting the spike protein. This work was originally reported in 2020 in the journal Science.
In the new work, the team redesigned the proteins – called minibinders – to make them even more potent. Rather than targeting a single site of the virus’s infectious machinery, minibinders bind to three sites simultaneously, making the drug less likely to come off.
“The SARS-CoV-2 spike protein has three binding domains, and common antibody therapies can only block one,” Jewett said. “Our mini binders sit on the spike protein like a tripod and block all three. The interaction between the spike protein and our antiviral is among the closest interactions known in biology. When we put the spike protein and our antiviral therapeutic in a test tube together for a week, they stayed connected and never separated. »
Jewett is a professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and director of Northwestern’s Center for Synthetic Biology. Andrew C. Hunt, a graduate researcher in Jewett’s lab, is the paper’s co-first author.
As the SARS-CoV-2 virus has mutated to create new variants, some treatments have become less effective in fighting the ever-evolving virus. Last month, the FDA suspended several monoclonal antibody treatments, for example, due to their failure against the BA.2 omicron subvariant.
Unlike these antibody treatments, which failed to neutralize omicron, the new minibinders maintained their efficacy against the concerning omicron variant. By blocking the virus’ spike protein, the new antiviral prevents it from binding to the human angiotensin-converting enzyme 2 (ACE2) receptor, which is the entry point for infecting the body. Since the new coronavirus and its mutant variants cannot infect the body without binding to the ACE2 receptor, the antiviral should also work against future variants.
“To enter the body, the spike protein and the ACE2 receptor engage in a handshake,” Jewett said. “Our antiviral blocks that handshake and, as a bonus, resists viral escape. »
In addition to losing effectiveness, current antibody therapies also have several problems: they are difficult to develop, expensive and require a medical professional to administer. They also require complicated supply chains and extreme refrigeration, which is often unavailable in low-resource settings.
The new antiviral solves all these problems. Unlike monoclonal antibodies, which are made by cloning and growing live mammalian cells, the new antiviral treatment is produced at scale in microorganisms like E. coli, making them more cost-effective to manufacture. Not only is the new therapy stable at high temperatures, which could further streamline manufacturing and reduce the cost of products for clinical development, but it also holds promise for being self-administered as a single nasal spray, thereby obviating the need of health professionals.
The researchers imagine that it could be available in pharmacies and used as a preventive measure to treat infections.
This study, “Multivalent Engineered Proteins Neutralize SARS-CoV-2 Variants of Concern and Confer Protection Against Infection in Mice,” was supported by The Audacious Project at the Institute for Protein Design; Bill & Melinda Gates Foundation (OPP1156262, INV-004949); Burroughs Welcoming Fund; Camille Dreyfus teacher-researcher program; David and Lucile Packard Foundation; Helen Hay Whitney Foundation; Open philanthropy project; Pew Biomedical Scholars Award; Schmidt futures contracts; Wu Tsai Translational Research Fund; Howard Hughes Medical Institute, including a fellowship from the Damon Runyon Cancer Research Foundation; Department of Defense (NDSEG-36373, W81XWH-21-1-0006, W81XWH-21-1-0007, W81XWH-20-1-0270-2019, AI145296 and AI143265); Defense Advanced Research Project Agency (HR0011835403 contract FA8750-17-C-0219); Defense Threat Reduction Agency (HDTRA1-15-10052, HDTRA1-20-10004); European Commission (MSCA CC-LEGO 792305); National Institutes of Health (1P01GM081619, R01GM097372, R01GM083867, T32GM007270, S10OD032290); National Institute of Allergy and Infectious Diseases (DP1AI158186, HHSN272201700059C, R37 AI1059371, R01 AI145486); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK117914, R01DK130386, U01DK127553, F31DK130550); National Institute of General Medical Sciences (R01GM120553); NHLBI Progenitor Cell Biology Consortium (U01HL099997, UO1HL099993); National Center for the Advancement of Translational Sciences (UG3TR002158); United Nations Global Antiviral Research Network; Quick Grants; T90 Training Grant; and with federal funds from the Department of Health and Human Services (HHSN272201700059C).