Divalent copper complexes as influenza A M2 inhibitors

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...

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Published in:	Antiviral research Vol. 147; pp. 100 - 106
Main Authors:	Gordon, Nathan A., McGuire, Kelly L., Wallentine, Spencer K., Mohl, Gregory A., Lynch, Jonathan D., Harrison, Roger G., Busath, David D.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-11-2017
Subjects:	Amantadine - pharmacology Animals Antiviral Agents - chemistry Antiviral Agents - pharmacology Cell Survival - drug effects Copper - chemistry Copper - pharmacology Copper - toxicity Dogs Dose-Response Relationship, Drug Drug Resistance, Viral - drug effects Drug Resistance, Viral - genetics Electrophysiology Humans Hydrophobic and Hydrophilic Interactions Influenza A Virus, H1N1 Subtype - drug effects Influenza A Virus, H1N1 Subtype - genetics Lethal Dose 50 Madin Darby Canine Kidney Cells Medicinal metals Mutation Plaque assay Proton transport Structure-Activity Relationship Therapeutic Index Transfected oocytes Tridentate chelation Viral Matrix Proteins - antagonists & inhibitors Viral Matrix Proteins - genetics Electrophysiology Transfected oocytes Tridentate chelation Plaque assay Medicinal metals Proton transport
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Summary:	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. [Display omitted] •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
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0166-3542 1872-9096
DOI:	10.1016/j.antiviral.2017.10.009