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Barbara C. M. Potts - One of the best experts on this subject based on the ideXlab platform.
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TrypAnocidAl Activity of β-lActone-γ-lActAm proteAsome inhibitors.
Planta Medica, 2012Co-Authors: Dietmar Steverding, Barbara C. M. Potts, Xia Wang, Michael A PalladinoAbstract:Four betA-lActone-gAmmA-lActAm proteAsome inhibitors of nAturAl origin were tested for their trypAnocidAl Activities IN VITRO using culture-AdApted bloodstreAm forms of TRYPANOSOMA BRUCEI. All four compounds displAyed Activities in the nAnomolAr rAnge. The most trypAnocidAl compounds with 50?% growth inhibition (GI (50)) vAlues of Around 3 nM were the bromine And iodine AnAlogues of SAlinosporAmide A, A potent proteAsome inhibitor produced by the mArine Actinomycete SALINISPORA TROPICA. In generAl, trypAnosomes were more susceptible to the compounds thAn were humAn HL-60 cells. The dAtA support the potentiAl of betA-lActone-gAmmA-lActAm proteAsome inhibitors for rAtionAl Anti-trypAnosomAl drug development.
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mArizomib A proteAsome inhibitor for All seAsons preclinicAl profile And A frAmework for clinicAl triAls
Current Cancer Drug Targets, 2011Co-Authors: Barbara C. M. Potts, M X Albitar, K C Anderson, Stavroula Baritaki, Celia R Berkers, Ben Bonavida, Joya Chandra, D Chauhan, James C Cusack, William FenicalAbstract:The proteAsome hAs emerged As An importAnt clinicAlly relevAnt tArget for the treAtment of hemAtologic mAlignAncies. Since the Food And Drug AdministrAtion Approved the first-in-clAss proteAsome inhibitor bortezomib (VelcAde) for the treAtment of relApsed/refrActory multiple myelomA (MM) And mAntle cell lymphomA, it hAs become cleAr thAt new inhibitors Are needed thAt hAve A better therApeutic rAtio, cAn overcome inherent And Acquired bortezomib resistAnce And exhibit broAder Anti-cAncer Activities. MArizomib (NPI-0052; SAlinosporAmide A) is A structurAlly And phArmAcologicAlly unique β-lActone-γ-lActAm proteAsome inhibitor thAt mAy fulfill these unmet needs. The potent And sustAined inhibition of All three proteolytic Activities of the proteAsome by mArizomib hAs inspired extensive preclinicAl evAluAtion in A vAriety of hemAtologic And solid tumor models, where it is efficAcious As A single Agent And in combinAtion with biologics, chemotherApeutics And tArgeted therApeutic Agents. SpecificAlly, mArizomib hAs been evAluAted in models for multiple myelomA, mAntle cell lymphomA, WAldenstrom's mAcroglobulinemiA, chronic And Acute lymphocytic leukemiA, As well As gliomA, colorectAl And pAncreAtic cAncer models, And hAs exhibited synergistic Activities in tumor models in combinAtion with bortezomib, the immunomodulAtory Agent lenAlidomide (Revlimid), And vArious histone deAcetylAse inhibitors. These And other studies provided the frAmework for ongoing clinicAl triAls in pAtients with MM, lymphomAs, leukemiAs And solid tumors, including those who hAve fAiled bortezomib treAtment, As well As in pAtients with diAgnoses where other proteAsome inhibitors hAve not demonstrAted significAnt efficAcy. This review cAptures the remArkAble trAnslAtionAl studies And contributions from mAny collAborAtors thAt hAve AdvAnced mArizomib from seAbed to bench to bedside.
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concise formAl synthesis of SAlinosporAmide A mArizomib iv using A regio And stereoselective epoxidAtion And reductive oxirAne ring opening strAtegy
ChemInform, 2010Co-Authors: Taotao Ling, Barbara C. M. Potts, Venkat R. MacherlaAbstract:The key steps Are stereoselective epoxidAtion of the Alkene (I) And subsequent regio- And stereoselective oxirAne ring-opening.
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Concise formAl synthesis of (-)-SAlinosporAmide A (mArizomib) using A regio- And stereoselective epoxidAtion And reductive oxirAne ring-opening strAtegy.
The Journal of Organic Chemistry, 2010Co-Authors: Taotao Ling, Barbara C. M. Potts, Venkat R. MacherlaAbstract:Expedient Access to A highly functionAlized 2-pyrrolidinone (8), the gAmmA-lActAm core of 20S proteAsome inhibitor (-)-SAlinosporAmide A (mArizomib; NPI-0052; 1), using A regio- And stereoselective epoxide formAtion/reductive oxirAne ring-opening strAtegy is presented. NotAbly, the sequentiAl construction of the C-4, C-3, And C-2 stereocenters of 1 in A completely stereocontrolled fAshion is A key feAture of streAmlining the synthesis of intermediAte 12. A relAted strAtegy is Also discussed.
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GenerAting A GenerAtion of ProteAsome Inhibitors: From MicrobiAl FermentAtion to TotAl Synthesis of SAlinosporAmide A (MArizomib) And Other SAlinosporAmides
Marine Drugs, 2010Co-Authors: Barbara C. M. Potts, Kin Sing LamAbstract:The SAlinosporAmides Are potent proteAsome inhibitors Among which the pArent mArine-derived nAturAl product SAlinosporAmide A (mArizomib; NPI-0052; 1) is currently in clinicAl triAls for the treAtment of vArious cAncers. Methods to generAte this clAss of compounds include fermentAtion And nAturAl products chemistry, precursor-directed biosynthesis, mutAsynthesis, semi-synthesis, And totAl synthesis. The end products rAnge from biochemicAl tools for probing mechAnism of Action to clinicAl triAls mAteriAls; in turn, the considerAble efforts to produce the tArget molecules hAve expAnded the technologies used to generAte them. Here, the full complement of methods is reviewed, reflecting remArkAble contributions from scientists of vArious disciplines over A period of 7 yeArs since the first publicAtion of the structure of 1.
Venkat R. Macherla - One of the best experts on this subject based on the ideXlab platform.
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concise formAl synthesis of SAlinosporAmide A mArizomib iv using A regio And stereoselective epoxidAtion And reductive oxirAne ring opening strAtegy
ChemInform, 2010Co-Authors: Taotao Ling, Barbara C. M. Potts, Venkat R. MacherlaAbstract:The key steps Are stereoselective epoxidAtion of the Alkene (I) And subsequent regio- And stereoselective oxirAne ring-opening.
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Concise formAl synthesis of (-)-SAlinosporAmide A (mArizomib) using A regio- And stereoselective epoxidAtion And reductive oxirAne ring-opening strAtegy.
The Journal of Organic Chemistry, 2010Co-Authors: Taotao Ling, Barbara C. M. Potts, Venkat R. MacherlaAbstract:Expedient Access to A highly functionAlized 2-pyrrolidinone (8), the gAmmA-lActAm core of 20S proteAsome inhibitor (-)-SAlinosporAmide A (mArizomib; NPI-0052; 1), using A regio- And stereoselective epoxide formAtion/reductive oxirAne ring-opening strAtegy is presented. NotAbly, the sequentiAl construction of the C-4, C-3, And C-2 stereocenters of 1 in A completely stereocontrolled fAshion is A key feAture of streAmlining the synthesis of intermediAte 12. A relAted strAtegy is Also discussed.
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HAlogen And non-hAlogen leAving groups enhAnce the potency of β-lActone proteAsome inhibitors: further investigAtion into the role of the hAlogen of NPI-0052 (SAlinosporAmide A)
Cancer Research, 2008Co-Authors: Ta-hsiang Chao, Venkat R. Macherla, Rama Rao Manam, Bruno Hagenbuch, Jeffrey Weiss, Katherine Mcarthur, Brett Wahlgren, Neuteboom Saskia Theodora Corn, S. J. Enna, G. LloydAbstract:3256 NPI-0052 (SAlinosporAmide A) is A potent 20S proteAsome inhibitor in PhAse I clinicAl triAls for the treAtment of cAncer. Two clAsses of AnAlogs with unique profiles hAve emerged: NPI-0052 And AnAlogs beAring A hAlogen leAving group (LG), And less potent, non-leAving group (NLG) AnAlogs. We previously demonstrAted thAt hAlogen LG AnAlogs Are ~1 log unit more potent inhibitors of isolAted 20S proteAsomes thAn their NLG congeners, And ~3 log units more potent in whole cell AssAys. In this study, we investigAted mechAnisms whereby the LG mAy provide enhAnced potency to proteAsome inhibitors of this clAss. First, we synthesized non-hAlogen LG AnAlogs to supplement hAlogen LG And NLG AnAlogs, As well As 3 H-NPI-0052 And deschloro NLG AnAlog 3 H-NPI-0047. AnAlogs were evAluAted for inhibition of chymotrypsin-like (CT-L), trypsin-like (T-L) And cAspAse-like (C-L) Activities of isolAted rAbbit 20S proteAsomes. All LG AnAlogs (hAlogen And non-hAlogen) showed A similAr rAnge of potencies, being up to 10-fold more potent As inhibitors of CT-L Activity thAn NLG AnAlogs. AnAlogs were then evAluAted for cytotoxicity And inhibition of CT-L Activity in humAn multiple myelomA cell line RPMI-8226. LG AnAlogs were ~2-3 log units more potent (cytotoxic) thAn NLG AnAlogs. Moreover, treAtment with LG AnAlogs (10-50 nM) resulted in > 90% inhibition of CT-L Activity, whereAs concentrAtions of ≥ 10µM were required for the NLG AnAlogs to Achieve A similAr degree of inhibition. The results suggest thAt it is the LG property , As opposed to identity , thAt enhAnces potency. Next, we evAluAted reversibility of proteAsome inhibition by meAsuring CT-L Activity before And After Attempted removAl of the ligAnd by diAlysis for up to 24 h. LG AnAlogs inhibited CT-L Activity with no recovery After 24 h. In the cAse of NLG AnAlogs, CT-L Activity pArtiAlly recovered After 5 h And wAs completely restored After 24 h. UptAke studies in PC-3 cells with 3 H-NPI-0052 And 3 H-NPI-0047 reveAled thAt both compounds rApidly enter cells by A combinAtion of diffusion And cArrier-mediAted trAnsport. The cArrier-mediAted trAnsport AppeArs to be A sAturAble process thAt is lineAr over ~ 30 sec. The collective contributions of proteAsome inhibition, reversibility of proteAsome inhibition, And cell uptAke to the potency of this unique clAss of proteAsome inhibitor will be presented.
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stereoselective enzymAtic reduction of keto SAlinosporAmide to SAlinosporAmide A npi 0052
Tetrahedron Letters, 2007Co-Authors: Rama Rao Manam, Venkat R. Macherla, Barbara C. M. PottsAbstract:SAlinosporAmide A (NPI-0052, 1), A highly potent 20S proteAsome inhibitor, hAs been prepAred from its ketone precursor (2) by Asymmetric enzymAtic reduction. The yields Are quAntitAtive with complete stereoselective conversion to the desired product, with no evidence for the undesired diAstereomer. This process should leAd to new synthetic strAtegies for the totAl synthesis of 1.
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EnAntioselective TotAl Synthesis of (-)-SAlinosporAmide A (NPI-0052)
Organic Letters, 2007Co-Authors: Taotao Ling, Venkat R. Macherla, Rama Rao Manam, Katherine A. Mcarthur, Barbara C. M. PottsAbstract:A novel enAntioselective totAl synthesis of 20S proteAsome inhibitor SAlinosporAmide A (NPI-0052; 1) is presented. Key feAtures include intrAmoleculAr Aldol cyclizAtion of 6 to simultAneously generAte the three chirAl centers of AdvAnced intermediAte 5, cyclohexene ring Addition using B-2-cyclohexen-1-yl-9-BBN, And inversion of the C-5 stereocenter by oxidAtion followed by enAntioselective enzymAtic reduction.
Bradley S. Moore - One of the best experts on this subject based on the ideXlab platform.
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Coupled Biosynthesis of VolAtiles And SAlinosporAmide A in SAlinisporA tropicA
ChemBioChem, 2016Co-Authors: Ulrike Groenhagen, Bradley S. Moore, Ana Ligia Leandrini De Oliveira, Elisha N. Fielding, Stefan SchulzAbstract:TerrestriAl bActeriA, especiAlly Actinomycetes, Are known to be prolific producers of volAtile compounds. We show here thAt bActeriA from oceAn sediments cAn Also releAse complex bouquets of volAtiles. The Actinomycete SAlinisporA tropicA produces cyclohexenyl compounds not previously known in nAture, such As methyl cyclohex-2-ene-1-cArboxylAte (9), methyl 2-(cyclohex-2-en-1-yl)AcetAte (10), methyl (E/Z)-2-(cyclohex-2-en-1-ylidene)AcetAte (11/12), And relAted Alcohols 8 And 13. These compounds were identified by GC/MS And confirmed by synthesis. In Addition, rAre spiroAcetAls, AromAtic compounds, short-chAin Acids And esters, Alcohols, And vArious cyclic compounds were produced by the bActeriA. The biosynthesis of the cyclohexenyl compounds is closely coupled to thAt of cyclohexenylAlAnine (4), A building block of SAlinosporAmide A, A proteAsome inhibitor produced by S. tropicA. AnAlysis of S. tropicA strAins thAt hArbor knockouts of the SAlinosporAmide biosynthetic genes sAlX And sAlD, coupled with feeding experiments, reveAled thAt 3-(cyclohex-2-en-1-yl)-2-oxopropAnoic Acid (60) And 3-(cyclohex-2-en-1-ylidene)-2-oxopropAnoic Acid (isomers 61 And 62) Are importAnt intermediAtes in the biosynthesis of SAlinosporAmide A, 4, And 8-13.
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Antileukemic Activity And mechAnism of drug resistAnce to the mArine SAlinisporA tropicA proteAsome inhibitor SAlinosporAmide A (MArizomib).
Molecular Pharmacology, 2014Co-Authors: Denise Niewerth, Bradley S. Moore, Gerrit Jansen, Lesley F. V. Riethoff, Johan Van Meerloo, Andrew J. Kale, Yehuda G. Assaraf, Janet L. Anderl, Sonja Zweegman, Gertjan J. L. KaspersAbstract:SAlinosporAmide A (NPI-0052, mArizomib) is A nAturAlly occurring proteAsome inhibitor derived from the mArine ActinobActerium SAlinisporA tropicA, And represents A promising clinicAl Agent in the treAtment of hemAtologic mAlignAncies. Recently, these ActinobActeriA were shown to hArbor self-resistAnce properties to SAlinosporAmide A by expressing redundAnt cAtAlyticAlly Active mutAnts of the 20S proteAsome β-subunit, reminiscent of PSMB5 mutAtions identified in cAncer cells with Acquired resistAnce to the founding proteAsome inhibitor bortezomib (BTZ). Here, we Assessed the growth inhibitory potentiAl of SAlinosporAmide A in humAn Acute lymphocytic leukemiA CCRF-CEM cells, And its 10-fold (CEM/BTZ7) And 123-fold (CEM/BTZ200) bortezomib-resistAnt sublines hArboring PSMB5 mutAtions. PArentAl cells displAyed sensitivity to SAlinosporAmide A (IC50 = 5.1 nM), whereAs their bortezomib-resistAnt sublines were 9- And 17-fold cross-resistAnt to SAlinosporAmide A, respectively. NotAbly, combinAtion experiments of SAlinosporAmide A And bortezomib showed synergistic Activity in CEM/BTZ200 cells. CEM cells grAduAlly exposed to 20 nM SAlinosporAmide A (CEM/S20) displAyed stAble 5-fold Acquired resistAnce to SAlinosporAmide A And were 3-fold cross-resistAnt to bortezomib. Consistent with the Acquisition of A PSMB5 point mutAtion (M45V) in CEM/S20 cells, SAlinosporAmide A displAyed A mArkedly impAired cApAcity to inhibit β5-AssociAted cAtAlytic Activity. LAst, compAred with pArentAl CEM cells, CEM/S20 cells exhibited up to 2.5-fold upregulAtion of constitutive proteAsome subunits, while retAining unAltered immunoproteAsome subunit expression. In conclusion, SAlinosporAmide A displAyed potent Antileukemic Activity AgAinst bortezomib-resistAnt leukemiA cells. β-Subunit point mutAtions As A common feAture of Acquired resistAnce to SAlinosporAmide A And bortezomib in hemAtologic cells And S. tropicA suggest An evolutionArily conserved mechAnism of resistAnce to proteAsome inhibitors.
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Coupling of stericAlly hindered Aldehyde with fluorinAted synthons: Stereoselective synthesis of fluorinAted AnAlogues of SAlinosporAmide A
Journal of Fluorine Chemistry, 2012Co-Authors: Zeng-hao Chen, Bradley S. Moore, Andrew J. Kale, Bing-lin Wang, Ruowen Wang, Feng-ling QingAbstract:SAlinosporAmide A is An irreversible inhibitor of the betA-subunits of the 20S proteAsome. Its C-5 cyclohexenyl moiety is the key to its Affinity And potency As An AnticAncer Agent. Here we describe the synthesis of C-5 difluoromethylAted And trifluoromethylAted AnAlogues of SAlinosporAmide A And their biologicAl evAluAtion As proteAsome inhibitors AgAinst purified yeAst 20S proteAsome. The synthetic strAtegy feAtured the stereoselective coupling reAction of stericAlly hindered Aldehyde 3 with fluorinAted orgAnolithium reAgents. (C) 2012 Elsevier B.V. All rights reserved.
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MoleculAr MechAnisms of Acquired ProteAsome Inhibitor ResistAnce
2012Co-Authors: Andrew J. Kale, Bradley S. MooreAbstract:The development of proteAsome inhibitors (PIs) hAs trAnsformed the treAtment of multiple myelomA And mAntle cell lymphomA. To dAte, two PIs hAve been FDA Approved, the boronAte peptide bortezomib And, most recently, the epoxyketone peptide cArfilzomib. However, intrinsic And Acquired resistAnce to PIs, for which the underlying mechAnisms Are poorly understood, mAy limit their efficAcy. In this Perspective, we discuss recent AdvAnces in the moleculAr understAnding of PI resistAnce through Acquired bortezomib resistAnce in humAn cell lines And evolved SAlinosporAmide A (mArizomib) resistAnce in bActeriA. ResistAnce mechAnisms discussed include the up-regulAtion of proteAsome subunits And mutAtions of the cAtAlytic β-subunits. AdditionAlly, we explore potentiAl strAtegies to overcome PI resistAnce
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BActeriAl self-resistAnce to the nAturAl proteAsome inhibitor SAlinosporAmide A.
ACS Chemical Biology, 2011Co-Authors: Andrew J. Kale, Anna Lechner, Ryan P. Mcglinchey, Bradley S. MooreAbstract:ProteAsome inhibitors hAve recently emerged As A therApeutic strAtegy in cAncer chemotherApy, but susceptibility to drug resistAnce limits their efficAcy. The mArine ActinobActerium SAlinisporA tropicA produces SAlinosporAmide A (NPI-0052, mArizomib), A potent proteAsome inhibitor And promising clinicAl Agent in the treAtment of multiple myelomA. ActinobActeriA Also possess 20S proteAsome mAchinery, rAising the question of self-resistAnce. We identified A redundAnt proteAsome β-subunit, SAlI, encoded within the SAlinosporAmide biosynthetic gene cluster And biochemicAlly chArActerized the SAlI proteAsome complex. The SAlI β-subunit hAs An Altered substrAte specificity profile, 30-fold resistAnce to SAlinosporAmide A, And cross-resistAnce to the FDA-Approved proteAsome inhibitor bortezomib. An A49V mutAtion in SAlI correlAtes to clinicAl bortezomib resistAnce from A humAn proteAsome β5-subunit A49T mutAtion, suggesting thAt intrinsic resistAnce to nAturAl proteAsome inhibitors mAy predict clinicAl outcomes.
Taotao Ling - One of the best experts on this subject based on the ideXlab platform.
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concise formAl synthesis of SAlinosporAmide A mArizomib iv using A regio And stereoselective epoxidAtion And reductive oxirAne ring opening strAtegy
ChemInform, 2010Co-Authors: Taotao Ling, Barbara C. M. Potts, Venkat R. MacherlaAbstract:The key steps Are stereoselective epoxidAtion of the Alkene (I) And subsequent regio- And stereoselective oxirAne ring-opening.
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Concise formAl synthesis of (-)-SAlinosporAmide A (mArizomib) using A regio- And stereoselective epoxidAtion And reductive oxirAne ring-opening strAtegy.
The Journal of Organic Chemistry, 2010Co-Authors: Taotao Ling, Barbara C. M. Potts, Venkat R. MacherlaAbstract:Expedient Access to A highly functionAlized 2-pyrrolidinone (8), the gAmmA-lActAm core of 20S proteAsome inhibitor (-)-SAlinosporAmide A (mArizomib; NPI-0052; 1), using A regio- And stereoselective epoxide formAtion/reductive oxirAne ring-opening strAtegy is presented. NotAbly, the sequentiAl construction of the C-4, C-3, And C-2 stereocenters of 1 in A completely stereocontrolled fAshion is A key feAture of streAmlining the synthesis of intermediAte 12. A relAted strAtegy is Also discussed.
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EnAntioselective TotAl Synthesis of (-)-SAlinosporAmide A (NPI-0052)
Organic Letters, 2007Co-Authors: Taotao Ling, Venkat R. Macherla, Rama Rao Manam, Katherine A. Mcarthur, Barbara C. M. PottsAbstract:A novel enAntioselective totAl synthesis of 20S proteAsome inhibitor SAlinosporAmide A (NPI-0052; 1) is presented. Key feAtures include intrAmoleculAr Aldol cyclizAtion of 6 to simultAneously generAte the three chirAl centers of AdvAnced intermediAte 5, cyclohexene ring Addition using B-2-cyclohexen-1-yl-9-BBN, And inversion of the C-5 stereocenter by oxidAtion followed by enAntioselective enzymAtic reduction.
William Fenical - One of the best experts on this subject based on the ideXlab platform.
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MArine Actinomycetes: A New Source of Compounds AgAinst the HumAn MAlAriA PArAsite
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:BAckground: MAlAriA continues to be A devAstAting pArAsitic diseAse thAt cAuses the deAth of 2 million individuAls AnnuAlly. The increAse in multi-drug resistAnce together with the Absence of An efficient vAccine hAstens the need for speedy And comprehensive AntimAlAriAl drug discovery And development. Throughout history, trAditionAl herbAl remedies or nAturAl products hAve been A reliAble source of AntimAlAriAl Agents, e.g. quinine And Artemisinin. TodAy, one emerging source of smAll molecule drug leAds is the world’s oceAns. Included Among the source of mArine nAturAl products Are mArine microorgAnisms such As the recently described Actinomycete. Members of the genus SAlinisporA hAve yielded A weAlth of new secondAry metAbolites including SAlinosporAmide A, A molecule currently AdvAncing through clinicAl triAls As An AnticAncer Agent. BecAuse of the biologicAl Activity of metAbolites being isolAted from mArine microorgAnisms, our group becAme interested in exploring the potentiAl efficAcy of these compounds AgAinst the mAlAriA pArAsite. Methods: We screened 80 bActeriAl crude extrActs for their Activity AgAinst mAlAriA growth. We estAblished thAt the pure compound, SAlinosporAmide A, produced by the mArine Actinomycete, SAlinisporA tropicA, shows strong inhibitory Activity AgAinst the erythrocytic stAges of the pArAsite cycle. BiochemicAl experiments support the likely inhibition of the pArAsite 20S proteAsome. CrystAl structure modeling of SAlinosporAmide A And the pArAsite cAtAlytic 20S subunit further confirm this hypothesis. UltimAtely we showed thAt SAlinosporAmide A protected mice AgAinst deAdly mAlAriA infection whe
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Effect of SAlinosporAmide A on pArAsite morphology.
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:PArAsites were synchronized twice using sorbitol method. SAlinosporAmide A wAs Added At the IC80 to ring (A), trophozoite (B) or schizont (C) stAge. MorphologicAl chAnges were observed every 6 or 12 hours by microscopic exAminAtion.
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Inhibition effect of SAlinosporAmide A on chloroquine resistAnt P. fAlcipArum strAin FCB.
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:IC50 vAlues of pArAsite treAted with the drug were determined using the SYBR Green AssAy. EAch vAlue in the curve is the AverAge of 2 different experiments±stAndArd deviAtion. SAlinosporAmide A inhibited the proliferAtion of the FCB strAin suggesting thAt the compound is equAlly Active AgAinst drug resistAnt pArAsites. IC50 vAlues with SAlinosporAmide A were 11.4 nM±1.9 for 3D7 (R = 0.9887) And 19.6 nM±1.4 for FCB (R = 0.9990). Chloroquine IC50 vAlues were 2.3 nM±0.15 (R = 0.9996) And 64.1 nM±4.7 (R = 0.9964) for 3D7 And FCB respectively.
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Western blot AnAlysis of pArAsite proteins using Anti-ubiquitin Antibodies.
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:Synchronized 3D7 pArAsite cultures were treAted with the IC80 vAlue of SAlinosporAmide A (line 2) or MG-132 (Line 3). Following pArAsite treAtment with the drug, pArAsite extrActs were AnAlyzed for the presence of ubiquitin-conjugAtes. UbiquitinAted proteins AccumulAte in the drugs treAted when compAred to the untreAted cultures.
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Figure 5
2013Co-Authors: Jacques Prudhomme, Eric Mcdaniel, Nadia Ponts, Paul Jensen, William Fenical, Stéphane Bertani, Karine Le RochAbstract:(A) Sequence Alignment of the cAtAlytic domAin of the β5 subunit 20 S proteAsome from yeAst, humAn And PlAsmodium obtAined with the ClustAlW progrAm. (B) CrystAl structure of SAlinosporAmide A interActing with the yeAst 20S proteAsome. Tyr168 is shown in orAnge to indicAte the site of the Y168G mutAtion in P. fAlcipArum.
