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High-content screening of natural products reveals novel nuclear export inhibitors

2014-01Journal article Restricted access
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dc.contributor.authorCautain, Bastien
dc.contributor.authorde Pedro, Nuria
dc.contributor.authorGarzon, Virginia Murillo
dc.contributor.authorde Escalona, Maria Munoz
dc.contributor.authorMenendez, Victor Gonzalez
dc.contributor.authorTormo, Jose R.
dc.contributor.authorMartin, Jesus
dc.contributor.authorEl Aouad, Noureddine
dc.contributor.authorReyes, Fernando
dc.contributor.authorAsensio, Francisco
dc.contributor.authorGenilloud, Olga
dc.contributor.authorVicente, Francisca
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2018-12-07T14:53:09Z
dc.date.available2018-12-07T14:53:09Z
dc.date.issued2014-01
dc.description.abstractNatural products are considered an extremely valuable source for the discovery of new drugs against diverse pathologies. As yet, we have only explored a fraction of the diversity of bioactive compounds, and opportunities for discovering new natural products leading to new drugs are huge. In the present study, U2nesRELOC, a previously established cell-based imaging assay, was employed to screen a collection of extracts of microbial origin for nuclear export inhibition activity. The fluorescent signal of untreated U2nesRELOC cells localizes predominantly to the cytoplasm. Upon treatment with the nuclear export inhibitor leptomycin B, the fluorescent-tagged reporter proteins appear as speckles in the nucleus. A proprietary collection of extracts from fungi, actinomycetes, and unicellular bacteria that covers an uncommonly broad chemical space was used to interrogate this nuclear export assay system. A two-step image-based analysis allowed us to identify 12 extracts with biological activities that are not associated with previously known active metabolites. The fractionation and structural elucidation of active compounds revealed several chemical structures with nuclear export inhibition activity. Here we show that substrates of the nuclear export receptor CRM1, such as Rev, FOXO3a and NF-B, accumulate in the nucleus in the presence of the fungal metabolite MDN-0105 with an IC50 value of 3.4 mu M. Many important processes in tumor formation and progression, as well as in many viral infections, critically depend on the nucleocytoplasmic trafficking of proteins and RNA molecules. Therefore, the disruption of nuclear export is emerging as a novel therapeutic approach with enormous clinical potential. Our work highlights the potential of applying high-throughput phenotypic imaging on natural product extracts to identify novel nuclear export inhibitors.
dc.description.sponsorshipFundacion MEDINA; MICINN [PCT-010000-2010-3]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1177/1087057113501389
dc.identifier.issn1087-0571
dc.identifier.issn1552-454X
dc.identifier.urihttp://hdl.handle.net/10400.1/11372
dc.language.isoeng
dc.peerreviewedyes
dc.publisherSage Publications Inc
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectLeptomycin-B
dc.subjectDrug discovery
dc.subjectAnticancer activity
dc.subjectTransport
dc.subjectSignals
dc.subjectCrm1
dc.subjectTranslocation
dc.subjectLocalization
dc.subjectProtein
dc.subjectCancer
dc.titleHigh-content screening of natural products reveals novel nuclear export inhibitors
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage65
oaire.citation.issue1
oaire.citation.startPage57
oaire.citation.titleJournal of Biomolecular Screening
oaire.citation.volume19
person.familyNameLink
person.givenNameWolfgang
person.identifier803637
person.identifier.ciencia-id6910-952E-242A
person.identifier.orcid0000-0002-3340-5165
person.identifier.scopus-author-id35368713800
rcaap.rightsrestrictedAccess
rcaap.typearticle
relation.isAuthorOfPublication12535e25-d71b-4a7f-9fc9-fff42d47deaf
relation.isAuthorOfPublication.latestForDiscovery12535e25-d71b-4a7f-9fc9-fff42d47deaf

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