Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

Abstract

Six series of semisynthetic lipophilic glycopeptide antibiotic derivatives were evaluated for in vitro activity against influenza A and B viruses. The new teicoplanin pseudoaglycon-derived lipoglycopeptides were prepared by coupling one or two side chains to the N-terminus of the glycopeptide core, using various conjugation methods. Three series of derivatives bearing two lipophilic groups were synthesized by attaching bis-alkylthio maleimides directly or through linkers of different lengths to the glycopeptide. Access to the fourth and fifth series of compounds was achieved by click chemistry, introducing single alkyl/aryl chains directly or through a tetraethylene glycol linker to the same position. A sixth group of semisynthetic derivatives was obtained by sulfonylation of the N-terminus. Of the 42 lipophilic teicoplanin pseudoaglycon derivatives tested, about half showed broad activity against influenza A and B viruses, with some of them having reasonable or no cytotoxicity. Minor differences in the side chain length as well as lipophilicity appeared to have significant impact on antiviral activity and cytotoxicity. Several lipoglycopeptides were also found to be active against human coronavirus.

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

“…However, antiviral activity proved accompanied by high cytotoxicity, probably due to a membrane-disrupting effect of the highly lipophilic side chains. [22] In addition, we found that cytotoxicity was reduced by decreasing the overall lipophilicity of the compounds following incorporation of a tetra(ethylene glycol) linker between the peptide core and the lipophilic group. [22] Hence, we assumed that attaching perfluoroalkyl groups that are highly hydro-and lipophobic might confer antiviral activity without creating a membrane-disrupting effect.…”

“…[22] In addition, we found that cytotoxicity was reduced by decreasing the overall lipophilicity of the compounds following incorporation of a tetra(ethylene glycol) linker between the peptide core and the lipophilic group. [22] Hence, we assumed that attaching perfluoroalkyl groups that are highly hydro-and lipophobic might confer antiviral activity without creating a membrane-disrupting effect. Namely, it has been shown that triphilic polymers bearing bulky and lipophobic perfluorinated blocks do not mix well with the hydrocarbon chains of lipids, explaining their low membrane partition coefficients.…”

“…Our recent results on semisynthetic lipoglycopeptides revealed that the type and length of the linkers significantly modifies the antiviral activity and cytotoxicity. [22] Herein, we have chosen the 1 a and 1 b allyl ethers of ethylene and tetra (ethylene glycol)s as linker chains between perfluoroalkyl substituents and the antibiotic molecules (Scheme 1). A lightpromoted atom-transfer radical addition reaction [28] of the commercially available perfluorobutyl iodide and perfluorooctyl iodide onto the double bond of 1 a and 1 b resulted in 2 a and 2 b, as well as 5 a and 5 b in good yields.…”

“…[15][16][17] In recent years, we conducted a systematic study on the synthesis of lipophilic derivatives of the glycopeptide antibiotics vancomycin, teicoplanin and ristocetin, and this yielded several new antibiotics with promising antibacterial and antiviral activity. [18][19][20][21][22] We demonstrated that the high lipophilicity of the side chains (C 8 À C 10 alkyl groups) in these molecules is essential for antiviral activity against, among others, influenza virus. However, antiviral activity proved accompanied by high cytotoxicity, probably due to a membrane-disrupting effect of the highly lipophilic side chains.…”

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

“…Recently, we prepared a series of teicoplanin pseudoaglycone (TC) derivatives by coupling one or two lipophilic side chains to the N-terminus of the glycopeptide core, using triazole, sulfonamide or maleimide linking elements [ 30 ]. Some of the modifications yielded remarkably effective inhibitors of influenza A and B viruses with low cytotoxicity.…”