Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Protein Cell. 2010 Mar;1(3):246-58. doi: 10.1007/s13238-010-0025-y. Epub 2010 Feb 23.
The M2 proteins of influenza A and B virus, AM2 and BM2, respectively, are transmembrane proteins that oligomerize in the viral membrane to form proton-selective channels. Proton conductance of the M2 proteins is required for viral replication; it is believed to equilibrate pH across the viral membrane during cell entry and across the trans-Golgi membrane of infected cells during viral maturation. In addition to the role of M2 in proton conductance, recent mutagenesis and structural studies suggest that the cytoplasmic domains of the M2 proteins also play a role in recruiting the matrix proteins to the cell surface during virus budding. As viral ion channels of minimalist architecture, the membrane-embedded channel domain of M2 has been a model system for investigating the mechanism of proton conduction. Moreover, as a proven drug target for the treatment of influenza A infection, M2 has been the subject of intense research for developing new anti-flu therapeutics. AM2 is the target of two anti-influenza A drugs, amantadine and rimantadine, both belonging to the adamantane class of compounds. However, resistance of influenza A to adamantane is now widespread due to mutations in the channel domain of AM2. This review summarizes the structure and function of both AM2 and BM2 channels, the mechanism of drug inhibition and drug resistance of AM2, as well as the development of new M2 inhibitors as potential anti-flu drugs.
甲型和乙型流感病毒的 M2 蛋白分别为 AM2 和 BM2，它们是跨膜蛋白，在病毒膜中寡聚形成质子选择性通道。M2 蛋白的质子传导对于病毒复制是必需的；它被认为在细胞进入时在病毒膜两侧以及在感染细胞的反式高尔基体膜中平衡 pH 值。除了 M2 在质子传导中的作用外，最近的突变和结构研究表明，M2 蛋白的细胞质结构域也在病毒出芽过程中招募基质蛋白到细胞膜表面方面发挥作用。作为具有极简架构的病毒离子通道，M2 的膜嵌入式通道结构域一直是研究质子传导机制的模型系统。此外，作为治疗甲型流感感染的有效药物靶标，M2 一直是开发新的抗流感治疗方法的研究热点。AM2 是两种抗甲型流感药物——金刚烷胺和金刚乙胺的靶标，它们都属于金刚烷类化合物。然而，由于 AM2 通道结构域的突变，甲型流感对金刚烷的耐药性现已广泛存在。本文总结了 AM2 和 BM2 通道的结构和功能、AM2 的药物抑制和耐药性机制，以及作为潜在抗流感药物的新型 M2 抑制剂的开发。
