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TitleComputational design of an ultrapotent deltacoronavirus miniprotein inhibitor.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 123, Issue 18, Page e2533456123, Year 2026
Publish dateMay 5, 2026
AuthorsNathan G Avery / Courtney N Yoshiyama / Ashley L Taylor / Young-Jun Park / Daniel Asarnow / Lisa Perruzza / Jack T Brown / Davide Corti / Fabio Benigni / Tyler N Starr / David Veesler /
PubMed AbstractMultiple spillovers of porcine deltacoronavirus (PDCoV) into humans in Haiti highlight its zoonotic potential and the need for targeted interventions. No approved vaccines or therapeutics are ...Multiple spillovers of porcine deltacoronavirus (PDCoV) into humans in Haiti highlight its zoonotic potential and the need for targeted interventions. No approved vaccines or therapeutics are available for use in humans against any DCoVs. Here, we report the de novo design of PDCoV miniprotein inhibitors (aka minibinders, MBs) and show that one of them, MB11, binds with picomolar affinity to the PDCoV receptor-binding domain (RBD). MB11 potently inhibits PDCoV, outcompeting monoclonal antibodies, and cross-reacts with and broadly neutralizes a panel of distantly related DCoVs. We determined a cryoelectron microscopy structure of MB11 bound to the PDCoV RBD which reveals the molecular basis of broad DCoV neutralization through interference with host receptor engagement. Deep mutational scanning of the PDCoV RBD reveals that MB11 has a high barrier to viral escape with only few mutations mediating escape without dampening APN receptor binding. MB11 resists stringent biochemical stresses, including high temperature, low pH, and proteolysis, which may enable delivery to various tissues for viral inhibition. This work delineates a prime candidate for clinical evaluation against PDCoV infection and for pandemic preparedness.
External linksProc Natl Acad Sci U S A / PubMed:42054371 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 2.84 Å
Structure data

EMDB-76232, PDB-11zv:
Structure of the Porcine deltacoronavirus (PDCoV) receptor-binding domain bound to the RBD minibinder 11, the PD3 Fab, and the Kappa light chain nanobody (local refinement)
Method: EM (single particle) / Resolution: 2.84 Å

EMDB-76233, PDB-11zw:
Structure of the Porcine deltacoronavirus (PDCoV) receptor-binding domain bound to the RBD minibinder 11, the PD3 Fab, and the Kappa light chain nanobody
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-HOH:
WATER

Source
  • porcine deltacoronavirus
  • synthetic construct (others)
  • mus musculus (house mouse)
  • lama glama (llama)
KeywordsVIRAL PROTEIN / porcine deltacoronavirus / minibinder / protein design / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID

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