Orthohantavirus-related Proteases as Therapeutic Targets: Opportunities for Antiviral Drug Development

Orthohantaviruses cause severe human diseases including hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), with case fatality rates up to 40%. No FDA-approved therapeutics are currently available, highlighting urgent need for drug development following recent outbreak events. We systematically examined host protease dependencies in hantavirus replication, focusing on Signal Peptidase (SP) and Signal Peptide Peptidase (SPP) essential for viral glycoprotein maturation. Through comprehensive database mining and molecular docking analysis, we identified six potential protease inhibitors, with Compound E achieving the highest binding confidence score (−0.28) against SPP. Our analysis reveals that targeting host ER proteases represents a viable antiviral strategy, providing a systematic framework for protease-targeted antihantavirus drug development and identifying specific lead compounds for experimental validation.