Discovery of Spiro-Piperidine Inhibitors and Their Modulation of the Dynamics of the M2 Proton Channel from Influenza A Virus

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• 作者：Jun Wang ; Sarah D. Cady ; Victoria Balannik ; Lawrence H. Pinto ; William F. DeGrado ; Mei Hong
• 刊名：Journal of the American Chemical Society
• 出版年：2009
• 出版时间：June 17, 2009
• 年：2009
• 卷：131
• 期：23
• 页码：8066-8076
• 全文大小：394K
• 年卷期：v.131,no.23(June 17, 2009)
• ISSN：1520-5126

文摘

Amantadine has been used for decades as an inhibitor of the influenza A virus M2 protein (AM2) in the prophylaxis and treatment of influenza A infections, but its clinical use has been limited by its central nervous system (CNS) side effects as well as emerging drug-resistant strains of the virus. With the goal of searching for new classes of M2 inhibitors, a structure−activity relation study based on 2-[3-azaspiro(5,5)undecanol]-2-imidazoline (BL-1743) was initiated. The first generation BL-1743 series of compounds has been synthesized and tested by two-electrode voltage-clamp (TEV) assays. The most active compound from this library, 3-azaspiro[5,5]undecane hydrochloride (9), showed an IC₅₀ as low as 0.92 ± 0.11 μM against AM2, more than an order of magnitude more potent than amantadine (IC₅₀ = 16 μM). ¹⁵N and ¹³C solid-state NMR was employed to determine the effect of compound 9 on the structure and dynamics of the transmembrane domain of AM2 (AM2-TM) in phospholipid bilayers. Compared to amantadine, spiro-piperidine 9 (1) induces a more homogeneous conformation of the peptide, (2) reduces the dynamic disorder of the G34-I35 backbone near the water-filled central cavity of the helical bundle, and (3) influences the dynamics and magnetic environment of more residues within the transmembrane helices. These data suggest that spiro-piperidine 9 binds more extensively with the AM2 channel, thus leading to stronger inhibitory potency.