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Divalent copper complexes as influenza A M2 inhibitors
Antiviral Research ( IF 7.6 ) Pub Date : 2017-10-12 , DOI: 10.1016/j.antiviral.2017.10.009
Nathan A. Gordon , Kelly L. McGuire , Spencer K. Wallentine , Gregory A. Mohl , Jonathan D. Lynch , Roger G. Harrison , David D. Busath

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.



中文翻译:

二价铜络合物作为甲型流感M2抑制剂

需要新型的M2阻滞剂,以有效抵抗甲型流感中普遍存在的耐金刚烷胺的S31N M2突变。六铜络合物,24689,和10,被合成并发现阻断野生型和S31N M2。游离Cu 2+也会阻止M2 S31N,但不会阻止S31N / H37A。铜络合物不会阻止M2 H37A(S31或S31N)。该复合物在细胞培养试验中可有效对抗三种甲型流感病毒,但对细胞的毒性不如CuCl 2。例如在所用的缓冲液中,pH(> 4)稳定的Cu(环辛基胺亚氨基二乙酸酯)的EC 50相对于A / Calif / 07/2009 H1N1为0.7±0.1μM,CC 50为147μM(治疗指数,三个菌株的平均值为67.8)。相反,CuCl 2的EC 50为3.8±0.9μM,CC 50为19μM。由于M2 H37是高度保守的,这些配合物显示出有望作为针对所有A型流感病毒的药物进行进一步测试的希望。

更新日期:2017-10-12
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