Zhang_2025_Hlife__

Coronaviruses (CoVs) pose a continual threat to global public health due to their broad host range and potential for cross-species transmission. Notable examples include the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, each causing worldwide health emergencies. Despite vaccine and antiviral development targeting these CoVs, new CoVs regularly emerge in animals, often without attracting significant attention. Recently, a novel MERS-like CoV, termed Manis javanica HKU4-related coronavirus 1 (MjHKU4r-CoV-1) was identified in pangolins. This virus demonstrates a high infectivity in human cells and organs, suggesting a potential risk for human infection. Importantly, due to limited sequence conservation between the receptor-binding domains (RBDs) of MERS-CoV and MjHKU4r-CoV-1, multiple neutralizing antibodies, such as m336, ZME2711, and ZME07117, do not neutralize MjHKU4r-CoV-1. This underscores the urgent need to develop the antivirals before this virus poses a public health threat. Beyond neutralizing antibodies, the use of soluble proteins derived from viral receptors, particularly those with enhanced binding affinity or multivalency, has shown promise in preventing viral entry. MERS-CoV and MjHKU4r-CoV-1 use dipeptidyl peptidase 4 (DPP4 or CD26) as a receptor for cell entry. CD26 binds the RBD of MERS-CoV and MjHKU4r-CoV-1 via a conserved mechanism, making it a promising target for affinity enhancement through structure-based design