Copper complexes have previously been developed to target His37 in influenza M2 and are effective blockers of both the wild type (WT) and the amantadineresistant M2S31N. Here, we report that the complexes were much less toxic to zebrafish than CuCl 2. In addition, we characterized albumin binding, mutagenicity, and virus resistance formation of these metal complexes, and employed steered molecular dynamics simulations to explore whether the complexes would fit in M2. We also examined their anti-viral efficacy in a multi-generation cell culture assay to extend the previous work with an initial-infection assay, discovering that this is complicated by cell culture medium components. The number of copper ions binding to bovine serum albumin (BSA) correlates well with the number of surface histidines and BSA binding affinity is low compared to M2. No mutagenicity of the complexes was observed when compared to sodium azide. After 10 passages of virus in MDCK culture, the EC 50 was unchanged for each of the complexes, i.e. resistance did not develop. The simulations revealed that the compounds fit well in the M2 channel, much like amantadine.

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