Evidence map›Paper›PMID 31175183›Full record

ArticleMolecular pharmacology2019

The L46P mutant confers a novel allosteric mechanism of resistance toward the influenza A virus M2 S31N proton channel blockers.

Rami Musharrafieh, Panagiotis I Lagarias, Chunlong Ma, Gene S Tan, Antonios Kolocouris, Jun Wang

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
1.8field-weighted citation impact, top 15% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed, 17 citations in OpenAlex.

  1. Review
  2. Article
  3. Antiviral Approaches against Influenza Virus.Clinical microbiology reviews · 2023
    Review
  4. Detection and Prevention of Virus Infection.Advances in experimental medicine and biology · 2022
    Article
  5. Article
  6. Article
  7. Review
  8. Article
  9. Article
  10. Review
  11. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 3 institutions in 2 countries.

Rami MusharrafiehDepartment of Pharmacology and Toxicology, College of Pharmacy (R.M., C.M., J.W.) and Department of Chemistry and Biochemistry (R.M.), University of Arizona, Tucson, Arizona; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Greece (P.I.L., A.K.); J. Craig Venter Institute, La Jolla, California (G.S.T.); and Department of Medicine, University of California, San Diego, La Jolla, California (G.S.T.).
Panagiotis I LagariasDepartment of Pharmacology and Toxicology, College of Pharmacy (R.M., C.M., J.W.) and Department of Chemistry and Biochemistry (R.M.), University of Arizona, Tucson, Arizona; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Greece (P.I.L., A.K.); J. Craig Venter Institute, La Jolla, California (G.S.T.); and Department of Medicine, University of California, San Diego, La Jolla, California (G.S.T.).
Chunlong MaDepartment of Pharmacology and Toxicology, College of Pharmacy (R.M., C.M., J.W.) and Department of Chemistry and Biochemistry (R.M.), University of Arizona, Tucson, Arizona; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Greece (P.I.L., A.K.); J. Craig Venter Institute, La Jolla, California (G.S.T.); and Department of Medicine, University of California, San Diego, La Jolla, California (G.S.T.).
Gene S TanDepartment of Pharmacology and Toxicology, College of Pharmacy (R.M., C.M., J.W.) and Department of Chemistry and Biochemistry (R.M.), University of Arizona, Tucson, Arizona; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Greece (P.I.L., A.K.); J. Craig Venter Institute, La Jolla, California (G.S.T.); and Department of Medicine, University of California, San Diego, La Jolla, California (G.S.T.).
Antonios KolocourisDepartment of Pharmacology and Toxicology, College of Pharmacy (R.M., C.M., J.W.) and Department of Chemistry and Biochemistry (R.M.), University of Arizona, Tucson, Arizona; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Greece (P.I.L., A.K.); J. Craig Venter Institute, La Jolla, California (G.S.T.); and Department of Medicine, University of California, San Diego, La Jolla, California (G.S.T.) ankol@pharm.uoa.gr.
Jun WangDepartment of Pharmacology and Toxicology, College of Pharmacy (R.M., C.M., J.W.) and Department of Chemistry and Biochemistry (R.M.), University of Arizona, Tucson, Arizona; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Greece (P.I.L., A.K.); J. Craig Venter Institute, La Jolla, California (G.S.T.); and Department of Medicine, University of California, San Diego, La Jolla, California (G.S.T.) junwang@pharmacy.arizona.edu.
University of Arizona · USNational and Kapodistrian University of Athens · GRJ. Craig Venter Institute · US

Funding

The J. Craig Venter Institute Genome Center for Infectious DiseasesU19AI110819 · NIAID · J. CRAIG VENTER INSTITUTE, INC. · PI NELSON, KAREN E., NIERMAN, WILLIAM CHARLES · 2014 to 2018
$29.7M
Drug Discovery Targeting the Influenza A Virus M2-S31N Proton ChannelR33AI119187 · NIAID · UNIVERSITY OF ARIZONA · PI PEREZ, DANIEL R, WANG, JUN · 2017 to 2019
$1.2M
Drug Discovery Targeting the Influenza A Virus M2-S31N Proton ChannelR21AI119187 · NIAID · UNIVERSITY OF ARIZONA · PI PEREZ, DANIEL R, WANG, JUN · 2015 to 2016
$419k
Discovery of broad-spectrum influenza antivirals with a high genetic barrier to drug resistance by targeting the viral polymeraseR21AI144887 · NIAID · UNIVERSITY OF ARIZONA · PI WANG, JUN · 2019 to 2020
$415k
NIAID NIH HHS R21 AI119187NIAID NIH HHS R21 AI144887NIAID NIH HHS R33 AI119187NIAID NIH HHS U19 AI110819
6 · The paper itself

Abstract

The Food and Drug Administration-approved influenza A antiviral amantadine inhibits the wild-type (WT) AM2 channel but not the S31N mutant predominantly found in circulating strains. In this study, serial viral passages were applied to select resistance against a newly developed isoxazole-conjugated adamantane inhibitor that targets the AM2 S31N channel. This led to the identification of the novel drug-resistant mutation L46P located outside the drug-binding site, which suggests an allosteric resistance mechanism. Intriguingly, when the L46P mutant was introduced to AM2 WT, the channel remained sensitive toward amantadine inhibition. To elucidate the molecular mechanism, molecular dynamics simulations and binding free energy molecular mechanics-generalized born surface area (MM-GBSA) calculations were performed on WT and mutant channels. It was found that the L46P mutation caused a conformational change in the N terminus of transmembrane residues 22-31 that ultimately broadened the drug-binding site of AM2 S31N inhibitor

Indexed as

MutationAllosteric RegulationAmantadineAmino Acid MotifsAnimalsAntiviral AgentsBinding SitesDogsDrug Resistance, ViralFemaleHumansInfluenza A virusMadin Darby Canine Kidney CellsModels, MolecularMolecular Dynamics SimulationProtein ConformationAmantadineAntiviral AgentsM2 protein, Influenza A virusViral Matrix ProteinsViroporin Proteins

Identifiers

PMID31175183
PMCPMC6608606
OpenAlexW2953788232

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.