Divalent copper complexes as influenza A M2 inhibitors

- Six copper complexes were synthesized and characterized for purity and stability.
- Copper iminodiacetates block M2 S31N channel currents irreversibly.
- The complexes block three strains of influenza from infecting cultured cells.
- Complex cytotoxicities against MDCK cells were lower than for uncomplexed Cu2+.
- The best average therapeutic index was 67.8

New M2 blockers effective against the ubiquitous amantadine-resistant S31N M2 mutation in influenza A are needed. Six copper complexes, 2, 4, 6, 8, 9, and 10, were synthesized and found to block both wild type and S31N M2. Free Cu2+ also blocks M2 S31N but not S31N/H37A. The copper complexes do not block M2 H37A (either S31 or S31N). The complexes were effective against three influenza A strains in cell-culture assays, but less toxic to cells than CuCl2. For example 4, Cu(cyclooctylamineiminodiacetate), which was stable at pH > 4 in the buffers used, had an EC50 against A/Calif/07/2009 H1N1 of 0.7 ± 0.1 μM with a CC50 of 147 μM (therapeutic index, averaged over three strains, 67.8). In contrast, CuCl2 had an EC50 of 3.8 ± 0.9 μM and CC50 of 19 μM. Because M2 H37 is highly conserved, these complexes show promise for further testing as drugs against all strains of influenza A.

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