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Divalent copper complexes as influenza A M2 inhibitors.
Nathan A Gordon1, Kelly L McGuire1, Spencer K Wallentine2
1Dept. of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
Antiviral Research
|October 17, 2017
Summary
New copper complexes effectively block amantadine-resistant influenza A M2 mutations. These compounds show promise as less toxic antiviral drugs against diverse influenza A strains.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- Influenza A virus relies on the M2 protein for replication.
- Amantadine resistance in influenza A is often caused by the S31N M2 mutation.
- Development of new M2 blockers is crucial to combat resistant influenza strains.
Purpose of the Study:
- To synthesize and evaluate novel copper complexes as M2 blockers.
- To assess the efficacy and toxicity of these complexes against wild-type and mutant M2 proteins.
- To explore their potential as antiviral agents against influenza A.
Main Methods:
- Synthesis of six copper complexes.
- In vitro testing of M2 blocking activity against wild-type and S31N mutant M2.
- Cell-culture assays using influenza A strains to determine EC50 and CC50 values.
- Evaluation of complex stability and toxicity.
Main Results:
- All six synthesized copper complexes blocked both wild-type and S31N M2 proteins.
- Free Cu2+ showed partial activity against M2 S31N but not S31N/H37A.
- Copper complexes demonstrated efficacy against three influenza A strains with lower cellular toxicity compared to CuCl2.
- Complex 4, Cu(cyclooctylamineiminodiacetate), exhibited a favorable therapeutic index (67.8).
Conclusions:
- Copper complexes are effective M2 blockers, including against amantadine-resistant strains.
- These complexes offer a potentially safer alternative to existing treatments due to reduced toxicity.
- The conserved nature of M2 H37 suggests these complexes could be broad-spectrum influenza A antivirals.