Significance
Multiple porcine deltacoronavirus (PDCoV) spillovers occurred in Haiti and there are currently no vaccines or therapeutics approved for use in humans. We computationally designed PDCoV miniprotein inhibitors and identified one (MB11) that potently and broadly neutralizes distantly related delta-coronaviruses. MB11 is resistant to multiple biochemical stresses, an ideal property for easy storage and delivery. These data pave the way for developing therapeutics to prepare for possible future PDCoV outbreaks.
Abstract
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.
Source:
Link: https://www.pnas.org/doi/abs/10.1073/pnas.2533456123?af=R
____
