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TitleThe computationally designed TRI2-2 miniprotein inhibitor protects against multiple SARS-CoV-2 Omicron variants.
Journal, issue, pagesCommun Biol, Year 2026
Publish dateJan 10, 2026
AuthorsJimin Lee / James Brett Case / Young-Jun Park / Rashmi Ravichandran / Daniel Asarnow / M Alejandra Tortorici / Jack T Brown / Shilpa Sanapala / Lauren Carter / David Baker / Michael S Diamond / David Veesler /
PubMed AbstractThe continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised neutralizing antibody responses elicited by prior infection or vaccination and abolished the ...The continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised neutralizing antibody responses elicited by prior infection or vaccination and abolished the utility of most monoclonal antibody therapeutics. We previously described a computationally-designed, homotrimeric miniprotein inhibitor, designated TRI2-2, that protects mice against pre-Omicron SARS-CoV-2 variants. Here, we show that TRI2-2 exhibits broadly neutralizing activity of SARS-CoV-2 variants and protects mice against BQ.1.1, XBB.1.5 and BA.2.86 challenge when administered intranasally post-exposure. The resistance of TRI2-2 to viral escape by most variants and the ability to deliver it directly to the upper airways highlight the potential of the multivalent miniprotein inhibitor as an alternative therapeutic modality.
External linksCommun Biol / PubMed:41519898
MethodsEM (single particle)
Resolution2.4 - 3.2 Å
Structure data

EMDB-45969, PDB-9cwp:
Local refinement of the SARS-CoV-2 BA.2.86 RBD in complex with TRI2-2 minibinder
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-45971, PDB-9cwq:
Local refinement of the SARS-CoV-2 BA.2.86 NTD
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-45972, PDB-9cwr:
SARS-CoV-2 BA.2.86 Spike trimer in complex with TRI2-2 minibinder
Method: EM (single particle) / Resolution: 2.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-HOH:
WATER

Source
  • Sarbecovirus sp.
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
KeywordsVIRAL PROTEIN / Sarbecoviruses / Spike glycoprotein / Structural Genomic / inhibitor / minibinder / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID

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