Inhibitors of the M2 Proton Channel Engage and Disrupt Transmembrane Networks of Hydrogen-Bonded Waters

Journal of the American Chemical Society
Jessica L ThomastonWilliam F DeGrado

Abstract

Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-molecule approach is often viewed as insufficient to achieve high affinity and specificity. Here we show that small molecules can enable potent inhibition by targeting key waters. The M2 proton channel of influenza A is the target of the antiviral drugs amantadine and rimantadine. Structural studies of drug binding to the channel using X-ray crystallography have been limited because of the challenging nature of the target, with the one previously solved crystal structure limited to 3.5 Å resolution. Here we describe crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 Å), rimantadine bound to M2 in both the Inwardclosed (2.00 Å) and Inwardopen (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free ...Continue Reading

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Citations

Jul 25, 2019·PLoS Neglected Tropical Diseases·Debajit DeyManidipa Banerjee
Dec 20, 2019·ELife·Jooyoung ParkDavid Baker
Aug 9, 2019·Chemical Science·Fatemeh M MirWilliam D Lubell
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Jan 23, 2021·The Journal of Physical Chemistry Letters·Yue Zhang, Qing-Chuan Zheng
Dec 18, 2019·Biochimica Et Biophysica Acta. Biomembranes·Athina KonstantinidiAntonios Kolocouris
Feb 25, 2021·Journal of Neural Transmission·Wojciech DanyszPeter Riederer
Jul 28, 2021·Journal of Chemical Information and Modeling·Balázs Zoltán ZsidóCsaba Hetényi
May 6, 2019·Journal of Medicinal Chemistry·Gaochan WuPeng Zhan
Jul 3, 2019·Journal of the American Chemical Society·Laura C WatkinsGregory A Voth
Jun 12, 2019·Journal of the American Chemical Society·Jessica L ThomastonWilliam F DeGrado
Aug 14, 2020·ACS Chemical Biology·Christina TzitzoglakiAntonios Kolocouris
Sep 17, 2020·Journal of the American Chemical Society·Laura C WatkinsGregory A Voth
Sep 4, 2021·Angewandte Chemie·Kumar Tekwani MovellanLoren B Andreas
Oct 26, 2021·Faraday Discussions·Huong T KratochvilWilliam F DeGrado
Oct 30, 2021·Journal of Chemical Information and Modeling·Dimitrios KolokourisAntonios Kolocouris
Nov 24, 2021·Analytical Chemistry·Julia A TownsendMichael T Marty

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