Computational #design of an ultrapotent #deltacoronavirus miniprotein #inhibitor

 

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

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Genomics insights reveal multi-year maintenance of a new #Deltacoronavirus infecting #Seabirds from Cagarras Island Archipelago Natural Monument, #Brazil

Abstract

Previous studies have identified various pathogens in seabirds, notably coronaviruses (CoVs) and influenza A viruses (IAVs), due to their potential to cause significant morbidity and mortality. The Cagarras Island Archipelago Natural Monument, located near Rio de Janeiro, Brazil, serves as nesting site for two species, the magnificent frigatebird (Fregata magnificens) and the brown booby (Sula leucogaster). Despite its ecological importance, no prior studies have investigated viral infections in these species, which share habitat interfaces with densely populated human areas. To address this gap, we sampled and tested seabirds for CoVs and IAVs from January 2022 to April 2024. Birds were captured and identified by species, age, and sex. Oropharyngeal and cloacal swabs, as well as blood samples, were collected. Viral RNA was extracted using the QIAamp Viral RNA Mini Kit, and the presence of IAVs was screened via real-time RT-PCR, while CoVs were screened using semi-nested RT-PCR. Sanger and metatranscriptomic sequencing were performed to identify viral strains and assess phylogenetic relationships. Of the 153 seabirds sampled, CoVs were detected in 6 individuals (9.1%) of F. magnificens and 16 individuals (18.4%) of S. leucogaster. No IAVs were found in either oropharyngeal or cloacal swabs, and all serum samples were negative for the presence of antibodies against the virus. We recovered two full deltacoronavirus genomes and eight additional draft genomes from S. leucogaster samples obtained from distinct sampling expeditions and additional enteroviruses, passeriviruses, and picornaviruses. Phylogenetic analysis revealed that the detected CoVs are closely related to avian deltacoronaviruses from environmental samples of S. leucogaster in the Sao Pedro and Sao Paulo Archipelago, indicating potential viral exchange between these seabird populations living at these distant islands. Moreover, multiple detections in different individuals at different time points are associated with specific Spike NTD deletions that have been shown to accumulate in immune escape lineages, supporting the long-term maintenance through new infections and reinfection of this virus in these bird populations. This is the first detection of CoVs in F. magnificens, highlighting their circulation in marine ecosystems. Further research is needed to understand the ecological and epidemiological implications, including potential cross-species transmission

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.06.19.660416v1

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