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dc.contributor.authorSumanadasa, Subathdrage DM
dc.contributor.authorGoodman, Christopher D
dc.contributor.authorLucke, Andrew J
dc.contributor.authorSkinner-Adams, Tina
dc.contributor.authorSahama, Ishani
dc.contributor.authorHaque, Ashraful
dc.contributor.authorTram, Anh Do
dc.contributor.authorMcFadden, Geoffrey I
dc.contributor.authorFairlie, David P
dc.contributor.authorAndrew, Katherine T
dc.date.accessioned2017-10-30T12:30:28Z
dc.date.available2017-10-30T12:30:28Z
dc.date.issued2012
dc.date.modified2013-06-07T05:54:02Z
dc.identifier.issn0066-4804
dc.identifier.doi10.1128/AAC.00030-12
dc.identifier.urihttp://hdl.handle.net/10072/48258
dc.description.abstractHistone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom3849
dc.relation.ispartofpageto3856
dc.relation.ispartofissue7
dc.relation.ispartofjournalAntimicrobial agents and Chemotherapy
dc.relation.ispartofvolume56
dc.rights.retentionY
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchInfectious agents
dc.subject.fieldofresearchMedical microbiology
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode310702
dc.subject.fieldofresearchcode3207
dc.subject.fieldofresearchcode3214
dc.titleAntimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionVersion of Record (VoR)
gro.facultyGriffith Sciences, Griffith Institute for Drug Discovery
gro.rights.copyright© 2012 American Society for Microbiology. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.date.issued2012
gro.hasfulltextFull Text
gro.griffith.authorAndrews, Katherine T.
gro.griffith.authorSkinner-Adams, Tina
gro.griffith.authorSumanadasa, Dulangi


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