Developing viral infection models is challenging when the entry receptor is unidentified, hindering the characterization of viruses with unknown receptors. For instance, the Coronaviridae family comprises hundreds of viruses, many of which have unknown entry receptors, limiting efforts to fully understand this important group of viruses with pandemic potential. In a recent study, Liu, Huang, Guo, McCallum et al. present a method to create functional, customized coronavirus receptors (CVRs), which could facilitate the development of infection models that do not rely on native receptors.

The authors’ approach uses a modular design, which combines different components to build artificial receptors that can be specifically targeted by viruses. They identified key features that help CVRs act like native receptors, enabling cleavage of the viral spike protein, membrane fusion and viral entry. Using this approach, the authors generated cells expressing CVRs for different coronaviruses, many of which have unknown native receptors, and demonstrated that a pan-sarbecovirus CVR supported the growth of certain viruses. By expressing a Pipistrellus bat coronavirus HKU5-specific CVR in cells, they successfully rescued authentic HKU5 viruses using a reverse genetics approach, and isolated an HKU5 strain from a bat swab sample, showcasing the method’s potential.