Evidence map›Paper›PMID 25453344›Full record

ArticleAntiviral research2014

Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs.

Parmjeet Randhawa, G Zeng, M Bueno, A Salgarkar, Andrew Lesniak, K Isse, K Seyb, A Perry, I Charles, C Hustus and 3 more

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

Article in Antiviral research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.3field-weighted citation impact, top 39% 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

5 citing papers in PubMed, 12 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Article
  5. 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

13 authors at 4 institutions in 1 country.

Parmjeet RandhawaUniversity of Pittsburgh, Pittsburgh, PA, USA. Electronic address: randhawapa@upmc.edu.
G ZengUniversity of Pittsburgh, Pittsburgh, PA, USA.
M BuenoUniversity of Pittsburgh, Pittsburgh, PA, USA.
A SalgarkarUniversity of Pittsburgh, Pittsburgh, PA, USA.
Andrew LesniakUniversity of Pittsburgh, Pittsburgh, PA, USA.
K IsseUniversity of Pittsburgh, Pittsburgh, PA, USA.
K SeybLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
A PerryLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
I CharlesLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
C HustusLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
M HuangLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
M SmithLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
Marcie A GlicksmanLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA.
University of Pittsburgh · USBrigham and Women's Hospital · USHarvard NeuroDiscovery Center · USHarvard University · US

Funding

National Center for Drug Discovery in NeurodegenerationU24NS049339 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI CUNY, GREGORY D · 2005 to 2009
$10.6M
NINDS NIH HHS NINDS 5U24NS049339NINDS NIH HHS U24 NS049339
6 · The paper itself

Abstract

introductionThis study evaluates polyomavirus JC (JCV) large T antigen (LTA) as a potential target for drug development. LTA is a hexameric protein with a helicase activity that is powered by ATP binding and hydrolysis. The helicase and ATPase function is critical for viral replication.

methodsRecombinant JCV LTA was produced in an Escherichia coli based expression plasmid. ATPase activity was measured using the malachite green assay. A high throughput screen was completed using a brain-biased library of 75,000 drug-like compounds selected for physicochemical properties consistent with blood-brain barrier permeability.

resultsFive compounds showed non-competitive inhibition of ATPase activity with an EC50 ⩽ 15 μM. Modest antiviral activity was demonstrated in an immunofluorescence assay for JCV VP-1 expression in COS7 cells (EC50 15, 18, 20, 27, and 52 μM respectively). The compounds also inhibited viral replication in a real time PCR assay at comparable concentrations. LD50 in the MTS96 and Cell TiterGlo assays was >100 μM for all compounds in COS7 as well as HEK293 cells. However, two compounds inhibited cell proliferation in culture with IC50 values of 43 and 34 μM respectively. Despite substantial amino acid similarity between polyomavirus JC, BK and SV40 proteins, these compounds differ from those previously reported to inhibit SV40 LTA ATPase in chemical structure as well as a non-competitive mechanism of inhibition.

conclusionLTA ATPase is a valid target for discovery. Additional screening and chemical optimization is needed to develop clinically useful compounds with less toxicity, which should be measured by metabolic as well as cell proliferation assays.

Indexed as

Adenosine TriphosphatasesAnimalsAntigens, Viral, TumorAntiviral AgentsCell LineChlorocebus aethiopsColorimetryDrug Evaluation, PreclinicalEnzyme InhibitorsEscherichia coliHigh-Throughput Screening AssaysHumansJC VirusRecombinant ProteinsVirus ReplicationAdenosine TriphosphatasesAntigens, Viral, TumorAntiviral AgentsEnzyme InhibitorsRecombinant ProteinsATPaseDrugsLarge T antigenPolyomavirus JC

Identifiers

PMID25453344
PMCPMC4258517
OpenAlexW2068052274

What OpenQuestion holds

Textmetadata
LicenceTDM
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.