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Abstract
Influenza A and B viruses are a global threat to human health and increasing resistance to the existing antiviral drugs necessitates new concepts to expand the therapeutic options. Glycopeptide derivatives have emerged as a promising new class of antiviral agents. To avoid potential antibiotic resistance, these antiviral glycopeptides are preferably devoid of antibiotic activity. We prepared six vancomycin aglycone hexapeptide derivatives with the aim of obtaining compounds having anti-influenza virus but no antibacterial activity. Two of them exerted strong and selective inhibition of influenza A and B virus replication, while antibacterial activity was successfully eliminated by removing the critical N-terminal moiety. In addition, these two molecules offered protection against several other viruses, such as herpes simplex virus, yellow fever virus, Zika virus, and human coronavirus, classifying these glycopeptides as broad antiviral molecules with a favorable therapeutic index.
Highlights
Seasonal infections by influenza A and B viruses are each year responsible for significant morbidity and mortality [1]
We reported a class of molecules with various lipophilic modifications at the N-terminal part of the peptide core of ristocetin, showing robust inhibition of influenza virus replication in cell culture [22]
That the antiviral activity of teicoplanin pseudoaglycone (TC) derivatives is primarily influenced by the structure of the side chains [30], we envisioned that we could reprogram vancomycin to create selective antiviral agents free of antibacterial activity by incorporating the appropriate lipophilic moieties of the former teicoplanins into vancomycin aglycone hexapeptide
Summary
Seasonal infections by influenza A and B viruses are each year responsible for significant morbidity and mortality [1]. As the antibacterial activity of these derivatives was a concern, the same researchers prepared and evaluated aminodecyl and adamantyl functionalized compounds with partially destroyed peptide cores [31] These degradation products lacking antibacterial activity typically displayed more-or-less weaker antiviral properties than the intact analogues. In the case of vancomycin or its aglycone, the N-terminal N-methyl-d-leucine moiety can be removed by Edman-degradation [35,36] yielding hexapeptide derivatives that are inactive against bacteria, likely due to their inability to bind to the target cell-wall precursors terminating in d-Ala-d-Ala. Since we previously determined, that the antiviral activity of TC derivatives is primarily influenced by the structure of the side chains [30], we envisioned that we could reprogram vancomycin to create selective antiviral agents free of antibacterial activity by incorporating the appropriate lipophilic moieties of the former teicoplanins into vancomycin aglycone hexapeptide
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