Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses.

Summary

HKU5 coronaviruses use ACE2 via a novel binding mode and can be enabled to use human ACE2 by a single amino acid change. The study maps species tropism determinants, identifies small-molecule inhibitors (including clinical compounds), and highlights antigenic divergence from MERS-CoV, informing outbreak preparedness.

Key Findings

• HKU5 uses ACE2 through a binding mode distinct from all other ACE2-using coronaviruses.
• A single amino acid mutation enables HKU5 to utilize human ACE2, highlighting a minimal barrier to spillover.
• HKU5 shows antigenic divergence from MERS-CoV and is susceptible to several inhibitors, including two clinical compounds.

Clinical Implications

Guides risk assessment of spillover by pinpointing minimal changes enabling human ACE2 usage and supports rapid development of therapeutics targeting HKU5-like lineages.

Limitations

• Lacks in vivo validation of spillover potential and transmission dynamics.
• Focuses on specific HKU5 clades; broader geographic and phylogenetic sampling is needed.

Future Directions

Evaluate human airway organoid and animal challenge models for HKU5 variants, optimize decoy ACE2 and inhibitor strategies, and integrate machine learning to prioritize surveillance.