Rationally optimized mucroporin-M1 peptides disrupt viral envelopes and resist degradation.

The increasing emergence of viral infections highlights the urgent need for new, broad-spectrum antiviral drugs. Peptide-based therapeutics, such as mucroporin-M1 derived from scorpion venom, offer promising antiviral potential due to their specificity and low toxicity. Here, we report on the design, synthesis, and structural and biological characterization of mucroporin-M1 analogues incorporating α-aminoisobutyric acid (Aib) residues and N-terminal lipidation to enhance helical stability and proteolytic resistance. Structural analyses via circular dichroism and NMR confirmed amphipathic helical conformations for some of the analogues. These modifications significantly improved resistance to enzymatic degradation and enhanced membranolytic activity. Biological evaluation showed that some peptides exert potent virucidal effects against enveloped RNA and DNA viruses belonging to the Flaviviridae or Herpesviridae family, with minimal cytotoxicity, while they are inactive against non-enveloped viruses. These findings suggest that chemically optimized mucroporin-M1 analogues can represent promising candidates for developing peptide-based antivirals endowed with broad-spectrum virucidal activity.