Scorpion venom peptide Hp1412 restricts enveloped virus replication by dampening virion infectivity

The majority of viruses considered as pandemic threats are enveloped viruses, structurally defined by lipids and integral viral envelope proteins. Scorpion venom contains an extremely diverse set of bioactive peptides, especially rich in antimicrobial agents. Here, we identified a 68-amino acid antimicrobial precursor protein Hp1412 from the venom gland of the scorpion Heterometrus petersii. Its 13-residue mature peptide was chemically synthesized and biochemically characterized. In vitro experiments demonstrated that Hp1412 exerted concentration-dependent inhibition on HCV RNA expression and exhibited low cell cytotoxicity. This peptide acted exclusively at the free virion stage of the HCV infection cycle, with optimal antiviral activity observed at 37°C. Further investigations revealed that Hp1412 possessed broad-spectrum antiviral activity against the tested enveloped viruses including IAV, HSV-1, VSV and SeV, whereas no significant inhibitory effect was observed against the non-enveloped virus EV71. These results suggested that the antiviral activity of Hp1412 was enveloped virus specific, and its underlying mechanism might involve direct interaction with free enveloped viral particles to disrupt their envelope structure. Further transmission electron microscopy analysis showed that Hp1412 inactivates IAV by directly disrupting the virion envelope. In vivo experiments showed that Hp1412 could prophylactically inhibit IAV replication in the lung tissues of mice, and significantly alleviate the excessive activation of innate immune responses and inflammatory reactions induced by IAV infection in lung tissues. Our study offers an initial clue that may inform the future development of broad-spectrum drugs for the prevention of enveloped virus infections.