XB-ART-43042
J Med Chem
2011 Apr 28;548:2646-57. doi: 10.1021/jm101334y.
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Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
Duque MD
,
Ma C
,
Torres E
,
Wang J
,
Naesens L
,
Juárez-Jiménez J
,
Camps P
,
Luque FJ
,
DeGrado WF
,
Lamb RA
,
Pinto LH
,
Vázquez S
.
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Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.
???displayArticle.pubmedLink??? 21466220
???displayArticle.pmcLink??? PMC3174104
???displayArticle.link??? J Med Chem
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R01 AI-57363 NIAID NIH HHS , U01 AI-1074571 NIAID NIH HHS , R01 AI020201-28 NIAID NIH HHS , R01 AI020201 NIAID NIH HHS , R01 AI057363 NIAID NIH HHS
References [+] :
Acharya,
Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus.
2010, Pubmed,
Xenbase
Acharya, Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus. 2010, Pubmed , Xenbase
Aigami, Biologically active polycycloalkanes. 1. Antiviral adamantane derivatives. 1975, Pubmed
Aldrich, Antiviral agents. 2. Structure-activity relationships of compounds related to 1-adamantanamine. 1971, Pubmed
Al-Nakib, Prevention and treatment of experimental influenza A virus infection in volunteers with a new antiviral ICI 130,685. 1986, Pubmed
Balannik, Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus. 2009, Pubmed , Xenbase
Balannik, Functional studies and modeling of pore-lining residue mutants of the influenza a virus M2 ion channel. 2010, Pubmed , Xenbase
Barril, Virtual screening in structure-based drug discovery. 2004, 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, Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. 2010, Pubmed
Cady, Structure and function of the influenza A M2 proton channel. 2009, 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
Camps, Synthesis of several halobisnoradamantane derivatives and their reactivity through the S(RN)1 mechanism. 2001, Pubmed
Camps, Synthesis and pharmacological evaluation of several ring-contracted amantadine analogs. 2008, Pubmed
Chen, Proton transport behavior through the influenza A M2 channel: insights from molecular simulation. 2007, Pubmed
Cui, Molecular dynamics-solvated interaction energy studies of protein-protein interactions: the MP1-p14 scaffolding complex. 2008, Pubmed
Deyde, Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. 2007, Pubmed
Duff, Neutron diffraction reveals the site of amantadine blockade in the influenza A M2 ion channel. 1994, Pubmed
Duque, Synthesis and pharmacological evaluation of (2-oxaadamant-1-yl)amines. 2009, Pubmed
García Martínez, Synthesis of substituted 1-norbornylamines with antiviral activity. 1995, Pubmed
Geluk, Synthesis and antiviral properties of 1-adamantylguanidine. A modified method for preparing t-alkylguanidines. 1969, Pubmed
Grambas, Maturation of influenza A virus hemagglutinin--estimates of the pH encountered during transport and its regulation by the M2 protein. 1992, Pubmed
Halgren, MMFF VI. MMFF94s option for energy minimization studies. 1999, Pubmed
Hien, Early pandemic influenza (2009 H1N1) in Ho Chi Minh City, Vietnam: a clinical virological and epidemiological analysis. 2010, Pubmed
Hornak, Comparison of multiple Amber force fields and development of improved protein backbone parameters. 2006, Pubmed
Hu, Identification of hits as matrix-2 protein inhibitors through the focused screening of a small primary amine library. 2010, Pubmed
Hu, Histidines, heart of the hydrogen ion channel from influenza A virus: toward an understanding of conductance and proton selectivity. 2006, Pubmed
Inamoto, Biologically active polycycloalkanes. 6. Antiviral 1-tricyclo[4.3.1.1 2,5]undecyl derivatives. 1979, Pubmed
Jing, Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel. 2008, Pubmed , Xenbase
Khurana, Computational study of drug binding to the membrane-bound tetrameric M2 peptide bundle from influenza A virus. 2011, Pubmed
Khurana, Molecular dynamics calculations suggest a conduction mechanism for the M2 proton channel from influenza A virus. 2009, Pubmed
Kolocouris, Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues. 2008, Pubmed
Kolocouris, Synthesis and antiviral activity evaluation of some aminoadamantane derivatives. 1994, Pubmed
Kolocouris, Synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2. 1996, Pubmed
Kolocouris, Design and synthesis of bioactive adamantane spiro heterocycles. 2007, 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
Lundahl, Synthesis and antiviral activities of adamantane spiro compounds. 1. Adamantane and analogous spiro-3'-pyrrolidines. 1972, Pubmed
Ma, Identification of the pore-lining residues of the BM2 ion channel protein of influenza B virus. 2008, Pubmed , Xenbase
Mathur, In vitro antiviral activity and preliminary clinical trials of a new adamantane compound. 1973, Pubmed
Morley, Validation of an empirical RNA-ligand scoring function for fast flexible docking using Ribodock. 2004, Pubmed
Naïm, Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 1. Exploring the parameter space. 2007, Pubmed
Ohigashi, An amantadine-sensitive chimeric BM2 ion channel of influenza B virus has implications for the mechanism of drug inhibition. 2009, Pubmed
Pebody, Pandemic Influenza A (H1N1) 2009 and mortality in the United Kingdom: risk factors for death, April 2009 to March 2010. 2010, Pubmed
Pinto, The M2 proton channels of influenza A and B viruses. 2006, Pubmed
Rosenberg, Coexistence of two adamantane binding sites in the influenza A M2 ion channel. 2010, Pubmed
Saito, Frequency of amantadine-resistant influenza A viruses during two seasons featuring cocirculation of H1N1 and H3N2. 2003, Pubmed
Schnell, Structure and mechanism of the M2 proton channel of influenza A virus. 2008, Pubmed
Scholtissek, How to overcome resistance of influenza A viruses against adamantane derivatives. 1998, Pubmed
Setaki, Synthesis, conformational characteristics and anti-influenza virus A activity of some 2-adamantylsubstituted azacycles. 2006, Pubmed
Skehel, Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. 2000, Pubmed
Smit, Synthesis and antiviral activities of adamantane spiro compounds. 2. 1972, 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
Stylianakis, Spiro[pyrrolidine-2,2'-adamantanes]: synthesis, anti-influenza virus activity and conformational properties. 2003, 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
Vanderlinden, Novel inhibitors of influenza virus fusion: structure-activity relationship and interaction with the viral hemagglutinin. 2010, Pubmed
Wang, Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. 2009, Pubmed , Xenbase
Whitney, Antiviral agents. I. Bicyclo [2.2.2] octan- and -oct-2-enamines. 1970, Pubmed
Yi, A secondary gate as a mechanism for inhibition of the M2 proton channel by amantadine. 2008, Pubmed
Zarubaev, Synthesis and anti-viral activity of azolo-adamantanes against influenza A virus. 2010, Pubmed
Zhirnov, Solubilization of matrix protein M1/M from virions occurs at different pH for orthomyxo- and paramyxoviruses. 1990, Pubmed
Zoidis, Are the 2-isomers of the drug rimantadine active anti-influenza A agents? 2003, Pubmed
Zoidis, Design and synthesis of 1,2-annulated adamantane piperidines with anti-influenza virus activity. 2009, Pubmed
Zoidis, Design and synthesis of bioactive 1,2-annulated adamantane derivatives. 2008, Pubmed
Zoidis, Heterocyclic rimantadine analogues with antiviral activity. 2006, Pubmed