Ajasja Ljubetič

Ajasja Ljubetič

Research Assistant Professor at the National Institute of Chemistry, Slovenia
Baker Lab alumni, MSCA fellow alumni.

Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice

AC Hunt, JB Case, Y-J Park, L Cao, K Wu, AC Walls, Z Liu, JE Bowen, H-W Yeh, S Saini, L Helms, YT Zhao, T-Y Hsiang, TN Starr, I Goreshnik, L Kozodoy, L Carter, R Ravichandran, LB Green, WL Matochko, CA Thomson, B Vögeli, A Krüger, LA VanBlargan, RE Chen, B Ying, AL Bailey, NM Kafai, SE Boyken, A Ljubetič, N Edman, G Ueda, CM Chow, M Johnson, A Addetia, M-J Navarro, N Panpradist, M Gale, BS Freedman, JD Bloom, H Ruohola-Baker, SPJ Whelan, L Stewart, MS Diamond, D Veesler, MC Jewett, D Baker
Science Translational Medicine, April 2022; doi: 10.1126/scitranslmed.abn1252

Highlights:

  • Designed antiviral proteins simultaneously bind to all three parts of SARS-CoV-2 spike protein.
  • Antiviral proteins neutralize all know SARS-CoV-2 variants, no escape mutants were found.
  • Antiviral proteins bind stronger than clinical antibodies and are cheaper to produce.
  • Application of antiviral proteins as nasal spray prevents infection in mice.

New variants of SARS-CoV-2 continue to arise, which is prolonging the pandemic. New variants also decrease the effectiveness of monoclonal antibody therapies. The SARS-CoV-2 spike protein is the key virulence factor of the virus. It is responsible for binding the virus to human cells. The spike protein is composed of three subunits. De novo designed antiviral protein binders offer a possible solution. Virus binding proteins have been designed; however they also lose the ability to bind the spike protein of new viral variants.

An international group of researchers, including dr. Ajasja Ljubetič from the Department of Synthetic Biology and Immunology of the National Institute of Chemistry have developed antiviral spike protein binders that are composed of triplets and designed to bind to all three subunits of the spike protein.
The trimer binding is much more potent: the binders neutralize all known variants of SARS-CoV-2 variants. In controlled experiments scientists tried to prepare variants of the spike protein that could not be neutralized by the new antiviral binders, but no such variants were not detected.
The antiviral binders are much easier to produce than monoclonal antibodies that are used in conventional therapies. The binders can be produced in bacteria and are resistant to heat, which enables cheap production and easier to scale up.
When the antiviral binders were administered into mice in the form of a nasal spray, the antiviral proteins reduced symptoms of infection or even prevented infection completely.

The research was led by Michael Jewett (Northwestern), Michael S. Diamond (Washington university) and David Veesler and David Baker (University of Washington). The first authors are Andrew C. Hunt, James Brett Case, Young-Jun Park, Longxing Cao, Kejia Wu and Alexandra C. Walls. Dr. Ajasja Ljubetič assisted in the computational method development for homotrimers, assisted in the computational design of the homotrimers and in linker and oligomer selection.

The results were published in the journal Science Translational Medicine (IF = 18).

Link: https://www.science.org/doi/10.1126/scitranslmed.abn1252

Contact for more information: ajasja.ljubetic(at)ki.si