Development and Characterization of Novel Antiviral Compounds Based on Plantaricins

The development of novel broad-spectrum antiviral agents is essential for addressing therapeutic gaps in managing common viral infections and the persistent threat of emerging and re-emerging pathogens. This thesis project investigated the antiviral properties of the antimicrobial peptides plantaricins. Study I demonstrated the broad-spectrum activityof PLNC8 ∝β, which disrupted viral envelopes and markedly reduced infectivity, with peptide’s efficacy depending on viral membrane composition. Study II further explored PLNC8 ∝β in a flavivirus infection model, revealing its ability to lower viral loads, attenuate infection-induced cytotoxicity, and modulate inflammation in alveolar epithelial cells. Study III assessed additional plantaricins, identifying truncated variants PLNC8 ∝1-15 and PLNC8 β1-20 as potent antiviral candidates. Synergistic activity was observed in certain complementary two-peptide combinations. Study IV evaluated PLNC8 ∝β’s safety in murine models, demonstrating good local tolerance and a favorable therapeutic window. Intranasal administration was well tolerated, while systemic toxicity occurred at high intravenous doses, highlighting the importance of optimized delivery strategies. Preliminary data on virus–bacteria co-infections indicated that PLNC8 ∝β exerted variable antiviral and antibacterial effects and reduced infection-induced cytotoxicity. Notably, keratinocytes exhibited resistance to the flavivirus Kunjin, suggesting intrinsic viral restriction and underscoring the need for further investigation using advanced models to clarify the role of PLNC8 ∝β in co-infections. Overall, this research supports plantaricins as promising broad-spectrum antiviral candidates. Future studies should focus on optimizing delivery and dosing regimens, exploring synergistic combinations, and applying advanced models to better understand their effects in the context of virus–bacteria co-infections.