RESUMEN

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.

Asunto(s)

Antivirales/farmacología , Cobre/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Proteínas de la Matriz Viral/antagonistas & inhibidores , Amantadina/farmacología , Animales , Antivirales/química , Supervivencia Celular/efectos de los fármacos , Cobre/química , Cobre/toxicidad , Perros , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral/genética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Subtipo H1N1 del Virus de la Influenza A/genética , Dosificación Letal Mediana , Células de Riñón Canino Madin Darby , Mutación , Relación Estructura-Actividad , Índice Terapéutico , Proteínas de la Matriz Viral/genética