Divalent copper complexes as influenza A M2 inhibitors.

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.

• Authors: Nathan A Gordon, Kelly L McGuire, Spencer K Wallentine, Gregory A Mohl, Jonathan D Lynch, Roger G Harrison, David D Busath
• Journal: Antiviral research (Antiviral Res) Vol. 147 Pg. 100-106 (Nov 2017) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 29032206 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• Antiviral Agents
• Viral Matrix Proteins
• Copper
• Amantadine
• cupric chloride

Topics

• Amantadine (pharmacology)
• Animals
• Antiviral Agents (chemistry, pharmacology)
• Cell Survival (drug effects)
• Copper (chemistry, pharmacology, toxicity)
• Dogs
• Dose-Response Relationship, Drug
• Drug Resistance, Viral (drug effects, genetics)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Influenza A Virus, H1N1 Subtype (drug effects, genetics)
• Lethal Dose 50
• Madin Darby Canine Kidney Cells
• Mutation
• Structure-Activity Relationship
• Therapeutic Index
• Viral Matrix Proteins (antagonists & inhibitors, genetics)