Antiviral Res. 2017 Nov;147:100-106. doi: 10.1016/j.antiviral.2017.10.009.

Divalent copper complexes as influenza A M2 inhibitors.

Gordon NA1, McGuire KL1, Wallentine SK2, Mohl GA1, Lynch JD2, Harrison RG3, Busath DD4.
1 Dept. of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
2 Dept. of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA.
3 Dept. of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA. Electronic address: roger_harrison@byu.edu.
4 Dept. of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. Electronic address: david_busath@byu.edu.

Abstract

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.

KEYWORDS: Electrophysiology; Medicinal metals; Plaque assay; Proton transport; Transfected oocytes; Tridentate chelation

PMID: 29032206

 

Supplement:

Metal complexes have many applications in medicine, including chemotherapy, radiological contrast, and antibiotics (ref). We reasoned that copper, a known ion channel blocker for the influenza A M2 channel (ref), might be adapted for use as an antiviral by complexing it to amantadine, the first discovered M2 blocker (ref). M2 has a critical and essentially completely conserved copper-binding histidine cluster in the heart of the channel at residue 37 (ref), but has grown resistant to amantadine through a nearby mutation at residue 31. In theory, the copper could act as an inescapable warhead at position 37, while the ligand amantadine, albeit with weakened binding because of the mutation at residue 31, could act as the delivery vehicle that both conveys the copper to its binding site while protecting cells from the toxic effects of the copper.

 

In this proof-of-principle publication, the concept of a protected copper-bearing warhead against the influenza A virus is validated. Imino-diacetate is identified as a prototype complexation moiety. Cyclooctylamine, another known influenza A M2 blocker, is shown to be as effective as amantadine for the ligand. Although the complexes tested were still too toxic for clinical use, the concept that ligation would be protective was demonstrated. This publication reports a first-in-class approach to an influenza antiviral that, through further optimization, could conceivably become useful as a universal influenza A therapeutic.​