Reprogramming of the Antibacterial Drug Vancomycin Results in Potent Antiviral Agents Devoid of Antibacterial Activity

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.

Keywords: antiviral; glycopeptide antibiotic; human coronavirus; influenza virus; vancomycin aglycone hexapeptide.

Scheme 1

Synthesis and structures of vancomycin aglycone hexapeptide derivatives 6–8 modified on the N-terminus. See Scheme 2 for the structures of alkynes 4 and 5.

Scheme 2

Structures of previously prepared alkynes 4 and 5 used for the synthesis of derivatives 6 and 7.

Scheme 3

Synthesis of amines 9-10 for the C-terminal modifications.

Scheme 4

Synthesis and structures of vancomycin aglycone hexapeptide (VAHP) derivatives 11–13 modified on the C-terminus.

Figure 1

Anti-influenza virus activity of compounds 6, 7, and 13, in MDCK cells at day 3 p.i. with A/PR/8/34 virus. (A) Representative images showing complete inhibition of viral cytopathic effect (CPE) at compound concentrations devoid of any cytotoxicity. (B) Reduction in virus yield, as determined by RT-qPCR for viral RNA in the supernatant (lower limit of detection: 10^1.6 copies). Curve fitting by GraphPad Prism, on two data points from one experiment performed in duplicate. Full grey line: Virus yield for untreated virus control; red dashed line: 100-fold reduction in virus yield. (C) Compound cytotoxicity in mock-infected cells, determined by MTS cell viability assay (mean data from three experiments). Full grey line: 100% viability in the cell control receiving no compound; red dashed line: 50% cell viability.

Figure 2

Activity of compound 6 in human embryonic lung (HEL) cells infected with human coronavirus 229E. (A) Representative images showing complete inhibition of viral CPE at non-toxic compound concentrations (reference compound: UDA lectin). (B) Reduction in virus yield, as determined by RT-qPCR for viral RNA in the supernatant at day 4 p.i. (lower limit of detection: 10² copies). Curve fitting by GraphPad Prism, on two data points from one experiment performed in duplicate. Full grey line: virus yield for untreated virus control; red dashed line: 100-fold reduction in virus yield.