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Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels.
Tzitzoglaki, Christina; McGuire, Kelly; Lagarias, Panagiotis; Konstantinidi, Athina; Hoffmann, Anja; Fokina, Natalie A; Ma, Chulong; Papanastasiou, Ioannis P; Schreiner, Peter R; Vázquez, Santiago; Schmidtke, Michaela; Wang, Jun; Busath, David D; Kolocouris, Antonios.
  • Tzitzoglaki C; Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens 15771, Greece.
  • McGuire K; Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah 84602, United States.
  • Lagarias P; Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens 15771, Greece.
  • Konstantinidi A; Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens 15771, Greece.
  • Hoffmann A; Jena University Hospital, Department of Medical Microbiology, Section Experimental Virology, Hans Knoell Str. 2, D-07745 Jena, Germany.
  • Fokina NA; Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany.
  • Ma C; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • Papanastasiou IP; Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens 15771, Greece.
  • Schreiner PR; Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany.
  • Vázquez S; Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona 08028, Spain.
  • Schmidtke M; Jena University Hospital, Department of Medical Microbiology, Section Experimental Virology, Hans Knoell Str. 2, D-07745 Jena, Germany.
  • Wang J; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • Busath DD; Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah 84602, United States.
  • Kolocouris A; Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens 15771, Greece.
ACS Chem Biol ; 15(9): 2331-2337, 2020 09 18.
Article in English | MEDLINE | ID: covidwho-1387140
ABSTRACT
We report on using the synthetic aminoadamantane-CH2-aryl derivatives 1-6 as sensitive probes for blocking M2 S31N and influenza A virus (IAV) M2 wild-type (WT) channels as well as virus replication in cell culture. The binding kinetics measured using electrophysiology (EP) for M2 S31N channel are very dependent on the length between the adamantane moiety and the first ring of the aryl headgroup realized in 2 and 3 and the girth and length of the adamantane adduct realized in 4 and 5. Study of 1-6 shows that, according to molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations, all bind in the M2 S31N channel with the adamantyl group positioned between V27 and G34 and the aryl group projecting out of the channel with the phenyl (or isoxazole in 6) embedded in the V27 cluster. In this outward binding configuration, an elongation of the ligand by only one methylene in rimantadine 2 or using diamantane or triamantane instead of adamantane in 4 and 5, respectively, causes incomplete entry and facilitates exit, abolishing effective block compared to the amantadine derivatives 1 and 6. In the active M2 S31N blockers 1 and 6, the phenyl and isoxazolyl head groups achieve a deeper binding position and high kon/low koff and high kon/high koff rate constants, compared to inactive 2-5, which have much lower kon and higher koff. Compounds 1-5 block the M2 WT channel by binding in the longer area from V27-H37, in the inward orientation, with high kon and low koff rate constants. Infection of cell cultures by influenza virus containing M2 WT or M2 S31N is inhibited by 1-5 or 1-4 and 6, respectively. While 1 and 6 block infection through the M2 block mechanism in the S31N variant, 2-4 may block M2 S31N virus replication in cell culture through the lysosomotropic effect, just as chloroquine is thought to inhibit SARS-CoV-2 infection.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Influenza A virus / Adamantane / Molecular Probes / Viral Matrix Proteins / Influenza, Human / Ion Channels Type of study: Experimental Studies / Randomized controlled trials Topics: Variants Limits: Humans Language: English Journal: ACS Chem Biol Year: 2020 Document Type: Article Affiliation country: ACSCHEMBIO.0C00553

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Influenza A virus / Adamantane / Molecular Probes / Viral Matrix Proteins / Influenza, Human / Ion Channels Type of study: Experimental Studies / Randomized controlled trials Topics: Variants Limits: Humans Language: English Journal: ACS Chem Biol Year: 2020 Document Type: Article Affiliation country: ACSCHEMBIO.0C00553