Evidence map›Paper›PMID 25477342›Full record

ArticleMolecular pharmacology2015

An integrated biological approach to guide the development of metal-chelating inhibitors of influenza virus PA endonuclease.

Annelies Stevaert, Salvatore Nurra, Nicolino Pala, Mauro Carcelli, Dominga Rogolino, Caitlin Shepard, Robert A Domaoal, Baek Kim, Mercedes Alfonso-Prieto, Salvatore A E Marras and 2 more

Abstract read
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In one paragraph

Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
–field-weighted citation impact
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

16 citing papers in PubMed.

  1. Pharmacophores of Influenza Virus PA Endonuclease Inhibitors.Advances in experimental medicine and biology · 2026
    Review
  2. Article
  3. Identification of Influenza PAMolecules (Basel, Switzerland) · 2021
    Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Review
  9. Article
  10. Review
  11. Article
  12. Article
  13. Article
  14. Article
  15. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2015
    Article
  16. 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

12 authors.

Annelies StevaertRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Salvatore NurraRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Nicolino PalaRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).ORCID http://orcid.org/0000-0002-9681-5233
Mauro CarcelliRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Dominga RogolinoRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Caitlin ShepardRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Robert A DomaoalRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Baek KimRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Mercedes Alfonso-PrietoRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Salvatore A E MarrasRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).
Mario SechiRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.).ORCID http://orcid.org/0000-0003-2983-6090
Lieve NaesensRega Institute for Medical Research, KU Leuven-University of Leuven, Leuven, Belgium (A.S., L.N.); Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy (S.N., N.P., M.S.); Department of Chemistry, University of Parma, Parma, Italy (M.C., D.R.); Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia (C.S., R.D., B.K.); Department of Pharmacy, Kyung-Hee University, Seoul, South Korea (B.K.); Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania (M.A.P.); and Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey (S.M.) lieve.naesens@rega.kuleuven.be.

Funding

Replication fidelity and lentiviral pathogenesisR01AI049781 · NIAID · UNIVERSITY OF ROCHESTER · PI KIM, BAEK · 2002 to 2016
$4.9M
NIAID NIH HHS R01 AI049781
6 · The paper itself

Abstract

The influenza virus PA endonuclease, which cleaves capped cellular pre-mRNAs to prime viral mRNA synthesis, is a promising target for novel anti-influenza virus therapeutics. The catalytic center of this enzyme resides in the N-terminal part of PA (PA-Nter) and contains two (or possibly one or three) Mg(2+) or Mn(2+) ions, which are critical for its catalytic function. There is great interest in PA inhibitors that are optimally designed to occupy the active site and chelate the metal ions. We focused here on a series of β-diketo acid (DKA) and DKA-bioisosteric compounds containing different scaffolds, and determined their structure-activity relationship in an enzymatic assay with PA-Nter, in order to build a three-dimensional pharmacophore model. In addition, we developed a molecular beacon (MB)-based PA-Nter assay that enabled us to compare the inhibition of Mn(2+) versus Mg(2+), the latter probably being the biologically relevant cofactor. This real-time MB assay allowed us to measure the enzyme kinetics of PA-Nter or perform high-throughput screening. Several DKA derivatives were found to cause strong inhibition of PA-Nter, with IC50 values comparable to that of the prototype L-742,001 (i.e., below 2 μM). Among the different compounds tested, L-742,001 appeared unique in having equal activity against either Mg(2+) or Mn(2+). Three compounds ( 10: , with a pyrrole scaffold, and 40: and 41: , with an indole scaffold) exhibited moderate antiviral activity in cell culture (EC99 values 64-95 μM) and were proven to affect viral RNA synthesis. Our approach of integrating complementary enzymatic, cellular, and mechanistic assays should guide ongoing development of improved influenza virus PA inhibitors.

Indexed as

AnimalsAntiviral AgentsChelating AgentsDogsDrug DiscoveryEndonucleasesHEK293 CellsHumansMadin Darby Canine Kidney CellsMolecular ConformationOrthomyxoviridaeAntiviral AgentsChelating AgentsEndonucleases

Identifiers

PMID25477342
PMCPMC11037440

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