Truncated Hs-1[7-20]mod peptide shows enhanced broad-spectrum antiviral activity with low-micromolar IC50s.

The global rise of antimicrobial resistance and the persistent threat of viral infections necessitate the development of novel broad-spectrum therapeutics. Current antiviral drugs often face challenges such as narrow specificity, rapid emergence of resistance, and significant side effects. Antimicrobial peptides (AMPs), derived from various natural sources, offer a promising scaffold due to their diverse mechanisms of action, including direct membrane disruption and modulation of host immune responses. This study addresses the urgent need for effective antiviral strategies by exploring and optimizing AMPs, specifically focusing on a peptide derived from Hypsiboas semilineatus, to overcome current therapeutic limitations.

Researchers applied a systematic sequence downsizing approach to the 20-amino-acid AMP Hs-1 from Hypsiboas semilineatus to identify its minimal active region. A series of N- and C-terminally truncated derivatives were synthesized, designed to preserve the predicted amphipathic α-helical core. Structural analysis using circular dichroism confirmed that these peptides adopt a random-coil conformation in aqueous solution, transitioning to an α-helical structure in hydrophobic environments, which is essential for membrane disruption. Antiviral screening was conducted against enveloped viruses, focusing on the early stages of infection. Further optimization involved N-terminal acetylation and C-terminal amidation of the most promising variant, Hs-1[7-20], to yield Hs-1[7-20]mod, with IC50 (half maximal inhibitory concentration) and CC50 (half maximal cytotoxic concentration) values as primary endpoints.