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J Am Chem Soc
2009 Jun 17;13123:8066-76. doi: 10.1021/ja900063s.
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Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus.
Wang J
,
Cady SD
,
Balannik V
,
Pinto LH
,
DeGrado WF
,
Hong M
.
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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 IC(50) as low as 0.92 +/- 0.11 microM against AM2, more than an order of magnitude more potent than amantadine (IC(50) = 16 microM). (15)N and (13)C 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.
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19469531
???displayArticle.pmcLink???PMC3807247 ???displayArticle.link???J Am Chem Soc ???displayArticle.grants???[+]
Abdel-Magid,
Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures(1).
1996, Pubmed
Abdel-Magid,
Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures(1).
1996,
Pubmed
Al-Nakib,
Prevention and treatment of experimental influenza A virus infection in volunteers with a new antiviral ICI 130,685.
1986,
Pubmed
Bright,
Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern.
2005,
Pubmed
Bright,
Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States.
2006,
Pubmed
Cady,
Determining the orientation of uniaxially rotating membrane proteins using unoriented samples: a 2H, 13C, AND 15N solid-state NMR investigation of the dynamics and orientation of a transmembrane helical bundle.
2007,
Pubmed
Cady,
Amantadine-induced conformational and dynamical changes of the influenza M2 transmembrane proton channel.
2008,
Pubmed
Cady,
Structure of amantadine-bound M2 transmembrane peptide of influenza A in lipid bilayers from magic-angle-spinning solid-state NMR: the role of Ser31 in amantadine binding.
2009,
Pubmed
Ciampor,
Evidence that the amantadine-induced, M2-mediated conversion of influenza A virus hemagglutinin to the low pH conformation occurs in an acidic trans Golgi compartment.
1992,
Pubmed
Czabotar,
Studies of structural changes in the M2 proton channel of influenza A virus by tryptophan fluorescence.
2004,
Pubmed
De Clercq,
Antiviral agents active against influenza A viruses.
2006,
Pubmed
Deyde,
Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide.
2007,
Pubmed
Fung,
An improved broadband decoupling sequence for liquid crystals and solids.
2000,
Pubmed
Gandhi,
Cu(II) inhibition of the proton translocation machinery of the influenza A virus M2 protein.
1999,
Pubmed
,
Xenbase
García Martínez,
Synthesis of substituted 1-norbornylamines with antiviral activity.
1995,
Pubmed
Giffin,
Novel assay for the influenza virus M2 channel activity.
1995,
Pubmed
,
Xenbase
Grambas,
Maturation of influenza A virus hemagglutinin--estimates of the pH encountered during transport and its regulation by the M2 protein.
1992,
Pubmed
Hay,
The molecular basis of the specific anti-influenza action of amantadine.
1985,
Pubmed
Hong,
Solid-state dipolar INADEQUATE NMR spectroscopy with a large double-quantum spectral width.
1999,
Pubmed
Hong,
Accurate measurement of methyl 13C chemical shifts by solid-state NMR for the determination of protein side chain conformation: the influenza a M2 transmembrane peptide as an example.
2009,
Pubmed
Hu,
Backbone structure of the amantadine-blocked trans-membrane domain M2 proton channel from Influenza A virus.
2007,
Pubmed
Hu,
Histidines, heart of the hydrogen ion channel from influenza A virus: toward an understanding of conductance and proton selectivity.
2006,
Pubmed
Ito,
Evolutionary analysis of the influenza A virus M gene with comparison of the M1 and M2 proteins.
1991,
Pubmed
Jing,
Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel.
2008,
Pubmed
,
Xenbase
Kolocouris,
Design and synthesis of bioactive adamantane spiro heterocycles.
2007,
Pubmed
Kolocouris,
Synthesis and antiviral activity evaluation of some aminoadamantane derivatives.
1994,
Pubmed
Kolocouris,
Synthesis of 2-(2-adamantyl)piperidines and structure anti-influenza virus A activity relationship study using a combination of NMR spectroscopy and molecular modeling.
1999,
Pubmed
Kolocouris,
Synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2.
1996,
Pubmed
Kurtz,
Growth impairment resulting from expression of influenza virus M2 protein in Saccharomyces cerevisiae: identification of a novel inhibitor of influenza virus.
1995,
Pubmed
Lagoja,
Anti-influenza virus agents: synthesis and mode of action.
2008,
Pubmed
Lamb,
Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface.
1985,
Pubmed
Li,
Solid-state NMR characterization of conformational plasticity within the transmembrane domain of the influenza A M2 proton channel.
2007,
Pubmed
London,
Dependence of amino acid side chain 13C shifts on dihedral angle: application to conformational analysis.
2008,
Pubmed
Luo,
Determination of the oligomeric number and intermolecular distances of membrane protein assemblies by anisotropic 1H-driven spin diffusion NMR spectroscopy.
2006,
Pubmed
Martin,
Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import.
1991,
Pubmed
Nishimura,
The closed state of a H+ channel helical bundle combining precise orientational and distance restraints from solid state NMR.
2002,
Pubmed
Ochiai,
Inhibitory effect of bafilomycin A1, a specific inhibitor of vacuolar-type proton pump, on the growth of influenza A and B viruses in MDCK cells.
1995,
Pubmed
Schnell,
Structure and mechanism of the M2 proton channel of influenza A virus.
2008,
Pubmed
Shimbo,
Ion selectivity and activation of the M2 ion channel of influenza virus.
1996,
Pubmed
,
Xenbase
Stamatiou,
Novel 3-(2-adamantyl)pyrrolidines with potent activity against influenza A virus-identification of aminoadamantane derivatives bearing two pharmacophoric amine groups.
2001,
Pubmed
Stamatiou,
Heterocyclic rimantadine analogues with antiviral activity.
2003,
Pubmed
Stouffer,
Structural basis for the function and inhibition of an influenza virus proton channel.
2008,
Pubmed
Tataridis,
Influence of an additional 2-amino substituent of the 1-aminoethyl pharmacophore group on the potency of rimantadine against influenza virus A.
2007,
Pubmed
Tu,
Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus.
1996,
Pubmed
,
Xenbase
Wang,
Structure of the transmembrane region of the M2 protein H(+) channel.
2001,
Pubmed
Wang,
Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
1993,
Pubmed
,
Xenbase
Winum,
N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide: a new sulfamyolating agent. Structure and reactivity toward amines.
2001,
Pubmed
Zhirnov,
Solubilization of matrix protein M1/M from virions occurs at different pH for orthomyxo- and paramyxoviruses.
1990,
Pubmed
Zoidis,
Design and synthesis of bioactive 1,2-annulated adamantane derivatives.
2008,
Pubmed
Zoidis,
Heterocyclic rimantadine analogues with antiviral activity.
2006,
Pubmed
