Amantadine copper(II) chloride conjugate with possible implementation in influenza virus inhibition

• Published in: Polyhedron 2020-07, Vol.185, p.114590, Article 114590
• Main Authors: Banti, C.N., Kourkoumelis, N., Hatzidimitriou, A.G., Antoniadou, Ivi, Dimou, A., Rallis, M., Hoffmann, A., Schmidtke, M., McGuire, K., Busath, D., Kolocouris, A., Hadjikakou, S.K.
• Format: Article
• Language: English
• Subjects: Amantadine; Amantadine-resistant A/WSN/33 M2 S31N mutation in influenza; Biological Inorganic chemistry; Copper(II) compound; Crystal structure; In silico study; Metals in biology
• ISSN: 0277-5387
• DOI: 10.1016/j.poly.2020.114590

1-Adamantanamine hydrochloride (AdNH3+ Cl−) is an antiviral drug that is used in the prophylactic or symptomatic treatment of influenza. However, a mutation makes influenza virus, amantadine (AdNH2) resistant. in order to overcome this disadvantage, a new formulation, which combines Cu(II) and amantadine (AdNH2) in one entity of formula {[AdNH3+]·[CuCl3]−}n, (CA) was developed. [Display omitted] •Copper(II) adamantanamines conjugates.•Mutations of influenza virus caused insensitivity to amantadine.•Blocking the proton current.•In vitro and vivo toxic toxicity effect. 1-Adamantanamine hydrochloride (AdNH3+ Cl−) is an antiviral drug that is used in the prophylactic or symptomatic treatment of influenza. However, a mutation makes influenza virus, amantadine (AdNH2) resistant. Thus, a new formulation, which combines Cu(II) and amantadine (AdNH2) in one formula {[AdNH3+]·[CuCl3]−}, (CA) was developed. CA was characterized by m.p, conductivity measurements, FT-IR and UV–Vis spectroscopies, and X-ray crystallography. To the best of our knowledge the crystal and molecular structure of CA is the first one of amantadine with Cu(II) ions. CA was tested against the A/WSN/33 wt (M2 N31) virus and its mutations M2 S31N, M2 V27A, M2 L26F, M2 A30T and M2 G34E respectively. CA inhibits the wild virus A/WSN/33 wt-M2 N31, and its mutations -M2 S31N, -M2 L26F and -M2 A30T. The inhibition mechanism involves the increased membrane permeability of the CA, than free Cu(II) ions with simultaneous lower toxicity. CA acts by blocking the proton current of A/WSN/33-M2 S31N in a similar manner to Cu(II) ions. In silico studies confirmed that CA can effectively block proton current mediated by -M2 S31N virus replication. Specifically, [CuCl3]− blocks the primary gate of the His37 tetrad which is essential for channel conductance and selectivity. The in vitro toxicity of CA was examined against normal human fetal lung fibroblast (MRC-5) cells. No toxic effect was detected when the MRC-5 cells were treated by CA with concentrations up to 30 μΜ. The absence of micronucleus (MN) in MRC-5 cells treated CA (30 μΜ) confirms the in vitro non genotoxic behavior of the compound. Moreover, no any in vivo toxic effect was detected on Artemia salina upon their treatment with CA at a concentration up to 150 μΜ.