A new protein-based antiviral nasal spray developed by researchers at Northwestern University, the University of Washington and Washington University in St. Louis is headed for phase I human clinical trials to treat COVID-19.
Computationally and sophisticatedly designed in the laboratory, new protein therapies thwart infection by interfering with the virus’s ability to enter cells. The top protein neutralized virus with equal or greater potency than the antibody treatment with emergency use authorization status from the US Food and Drug Administration (FDA). Notably, the top protein also neutralized all tested SARS-CoV-2 variants, something that many clinical antibodies have failed to do.
When researchers gave mice the treatment in the form of a nasal spray, they found that the best of these antiviral proteins reduced symptoms of infection — or even stopped infection altogether.
The findings were published yesterday (April 12) in the journal Science Translational Medicine.
The work was led by Michael Jewett of Northwestern; David Baker and David Wesler at the University of Washington School of Medicine; and Michael S. Diamond in Washoe.
To start, the team previously 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 remodeled the proteins — called minibinders — to make them even more potent. Instead of targeting only one site of the virus’s infectious machinery, the minibinder binds to three sites simultaneously, reducing the potential for drug separation.
“The spike protein of SARS-CoV-2 has three binding domains, and normal antibody treatments can only block one,” Jewett said. “Our minibinder sits on top of the spike protein like a tripod and blocks all three. The interaction between the spike protein and our antiviral is one of the tightest interactions known in biology. And put our antiviral therapeutics together in a test tube, so 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 the Northwestern Center for Synthetic Biology. Andrew C. Hunt, a graduate research fellow in Jewett’s lab, is a co-first author of the paper.
As the SARS-CoV-2 virus has mutated to form new variants, some treatments have become less effective at fighting the ever-evolving virus. Just last month, the FDA halted several monoclonal antibody therapies, for example, because of their failure against the BA.2 omicron subvariant.
The spike protein of SARS-CoV-2 has three binding domains, and normal antibody treatments can block only one. Our minibinder sits on top of the spike protein like a tripod and blocks all three.,
synthetic biologist
Unlike these antibody treatments, which failed to neutralize Omicron, the new minibinders maintained potency against the Omicron version of the concern. By blocking the virus’s 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. Because the novel coronavirus and its mutant forms cannot infect the body without binding to the ACE2 receptor, antivirals should also work against future variants.
“To enter the body, the spike protein and the ACE2 receptor engage in a handshake,” Jewett said. “Our antivirals prevent this handshake and, as a bonus, there is resistance to viral escape.”
In addition to losing effectiveness, current antibody treatments also come with a number of problems: they are difficult to develop, expensive and require a healthcare professional to administer them. They also require complex 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 culturing live mammalian cells, new antiviral treatments are produced on a large scale in microorganisms such as E. coli, making them more cost-effective to manufacture. Not only is the new therapy stable in high heat, which could further streamline manufacturing and reduce material costs for clinical development, it is also a one-time nasal spray, bypassing the need for medical professionals. It also holds the promise of being self-administered.
Researchers believe that it may be available at a pharmacy and used as a preventive measure to treat infections.
This study, “Multivalent designed proteins neutralize SARS-CoV-2 variants of anxiety and provide 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 Welcome Fund; Camille Dreyfus Teacher-Scholar Program; David and Lucille Packard Foundation; Helen Hay Whitney Foundation; Open Philanthropy Project; Pew Biomedical Scholars Award; Schmidt Futures; Wu Tsai Translational Investigator 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 Projects Agency (HR001835403 Annex 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 Advancing Translational Sciences (UG3TR002158); United World Antiviral Research Network; fast grants; T90 Training Grant; and with federal funds from the Department of Health and Human Services (HHSN272201700059C).
