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dc.contributor.authorLanglais, Daviden_US
dc.contributor.authorCencic, Reginaen_US
dc.contributor.authorMoradin, Nedaen_US
dc.contributor.authorKennedy, James M.en_US
dc.contributor.authorAyi, Kodjoen_US
dc.contributor.authorBrown, Lauren E.en_US
dc.contributor.authorCrandall, Ianen_US
dc.contributor.authorTarry, Michael J.en_US
dc.contributor.authorSchmeing, Martinen_US
dc.contributor.authorKain, Kevin C.en_US
dc.contributor.authorPorco, John A.en_US
dc.contributor.authorPelletier, Jerryen_US
dc.contributor.authorGros, Philippeen_US
dc.date.accessioned2018-08-13T19:20:31Z
dc.date.available2018-08-13T19:20:31Z
dc.date.issued2018-03-06
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000426671900028&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=6e74115fe3da270499c3d65c9b17d654
dc.identifier.citationDavid Langlais, Regina Cencic, Neda Moradin, James M Kennedy, Kodjo Ayi, Lauren E Brown, Ian Crandall, Michael J Tarry, Martin Schmeing, Kevin C Kain, John A Porco, Jerry Pelletier, Philippe Gros. 2018. "Rocaglates as dual-targeting agents for experimental cerebral malaria." Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2366-E2375. https://doi.org/10.1073/pnas.1713000115
dc.identifier.issn0027-8424
dc.identifier.urihttps://hdl.handle.net/2144/30767
dc.description.abstractCerebral malaria (CM) is a severe and rapidly progressing complication of infection by Plasmodium parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in Plasmodium parasites. Rocaglates are a class of natural products derived from plants of the Aglaia genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of Plasmodium falciparum eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with Plasmodium berghei (CM) and Plasmodium chabaudi (blood-stage malaria), and can also block replication of different clinical isolates of P. falciparum in human erythrocytes infected ex vivo, including drug-resistant P. falciparum isolates. In vivo, a single dosing of CR-1-31B in P. berghei-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in P. berghei-infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.en_US
dc.description.sponsorshipWe thank Susan Gauthier, Genevieve Perreault, and Patrick Senechal for technical assistance. This work was supported by a research grant (to P.G.) from the Canadian Institutes of Health Research (CIHR) (Foundation Grant). J.P. and P.G. are supported by a James McGill Professorship salary award. D.L. is supported by fellowships from the Fonds de recherche sante Quebec, the CIHR Neuroinflammation training program. J.P. is supported by CIHR Research Grant FDN-148366. M.S. is supported by a CIHR Foundation grant. J.A.P. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. K.C.K. was supported by a CIHR Foundation Grant and the Canada Research Chair program. (Canadian Institutes of Health Research (CIHR); James McGill Professorship salary award; Fonds de recherche sante Quebec; CIHR Neuroinflammation training program; FDN-148366 - CIHR Research Grant; CIHR Foundation grant; R35 GM118173 - NIH; Canada Research Chair program; R24 GM111625)en_US
dc.format.extentE2366 - E2375 (10)en_US
dc.languageEnglish
dc.publisherNational Academy of Sciencesen_US
dc.relation.ispartofPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
dc.relation.isversionof10.1073/pnas.1713000115
dc.subjectScience & technologyen_US
dc.subjectPlasmodiumen_US
dc.subjectCerebral malariaen_US
dc.subjectSevere malariaen_US
dc.subjectProtein translationen_US
dc.subjectDual targeten_US
dc.subjectArtemisinin resistanceen_US
dc.subjectTherapeutic suppressionen_US
dc.subjectTranslation inhibitorsen_US
dc.subjectAfrican childrenen_US
dc.subjectRandomized trialen_US
dc.subjectBlood stageen_US
dc.subjectT cellsen_US
dc.titleRocaglates as dual-targeting agents for experimental cerebral malariaen_US
dc.typeArticleen_US
pubs.elements-sourceweb-of-scienceen_US
pubs.notesEmbargo: Not knownen_US
pubs.organisational-groupBoston Universityen_US
pubs.organisational-groupBoston University, College of Arts & Sciencesen_US
pubs.organisational-groupBoston University, College of Arts & Sciences, Department of Chemistryen_US
pubs.publication-statusPublisheden_US


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