重新审视金刚烷胺对映体与甲型流感病毒M2蛋白的亲和力
Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited.
作者信息
Drakopoulos Antonios, Tzitzoglaki Christina, Ma Chulong, Freudenberger Kathrin, Hoffmann Anja, Hu Yanmei, Gauglitz Günter, Schmidtke Michaela, Wang Jun, Kolocouris Antonios
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , Athens, Greece.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona 85721, United States.
出版信息
ACS Med Chem Lett. 2017 Jan 27;8(2):145-150. doi: 10.1021/acsmedchemlett.6b00311. eCollection 2017 Feb 9.
Abstract
Recent findings from solid state NMR (ssNMR) studies suggested that the ()-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the ()-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.
摘要
固态核磁共振（ssNMR）研究的最新发现表明，金刚乙胺的（）-对映体与完整的M2蛋白结合的亲和力高于（）-对映体。受这些发现的启发，我们应用了功能测定法，如抗病毒测定法和电生理学（EP），来评估金刚乙胺对映体与M2蛋白通道的结合亲和力。出乎意料的是，两种对映体之间未发现显著差异。基于完整M2蛋白功能的实验数据得到了炼金术自由能计算和等温滴定量热法（ITC）的进一步支持，从而能够评估金刚乙胺对映体与M2跨膜孔的结合亲和力。两种对映体具有相似的通道阻断、亲和力和抗病毒效力。
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本文引用的文献
1
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2
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3
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J Chem Theory Comput. 2013 Feb 12;9(2):1272-81. doi: 10.1021/ct300899n. Epub 2013 Jan 3.
4
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J Phys Chem B. 2015 Sep 3;119(35):11548-59. doi: 10.1021/acs.jpcb.5b05808. Epub 2015 Aug 20.
5
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J Pharm Sci. 2015 Sep;104(9):3208-19. doi: 10.1002/jps.24508. Epub 2015 Jun 2.
6
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J Phys Chem B. 2015 Jan 22;119(3):1173-83. doi: 10.1021/jp506807y. Epub 2014 Nov 11.
7
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J Med Chem. 2014 Jun 12;57(11):4629-39. doi: 10.1021/jm500598u. Epub 2014 May 15.
8
Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds.新型多环胺类化合物抗流感病毒活性与病毒血凝素的作用。
Antiviral Res. 2013 Sep;99(3):281-91. doi: 10.1016/j.antiviral.2013.06.006. Epub 2013 Jun 22.
9
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10
Structural investigation of rimantadine inhibition of the AM2-BM2 chimera channel of influenza viruses.流感病毒 AM2-BM2 嵌合体通道中金刚烷胺抑制作用的结构研究。
Structure. 2011 Nov 9;19(11):1655-63. doi: 10.1016/j.str.2011.09.003.
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