Trypanosomatid Diseases (Molecular Routes to Drug Discovery) || Index

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    aacidocalcisomes 266activated protein-1 (AP-1) component 109active ligands 59active-site cysteine residue 183active smallmolecules, chemical structure 57adenosine ribose 139a-diuoromethylornithine (eornithine) 292AdoMetDC inhibitors 175ADP-ribosylation factor-like protein

    (ARL-1) 288AEP-1 247African sleeping sickness 57, 58, 405.

    See also Chagas diseaseAfrican trypanosomes 43, 184. See also

    human African trypanosomiasis (HAT) both TORC1 and TORC2 265 GLO2-encoding gene 157 human pathogenic stage 122 infective form 300, 301 lacking GLO1 161 necrosis, after H2O2 treatment 262 potential drug target 301 synthesis and reduction of

    trypanothione 388 treatments for 70 type IA DNA topoisomerases in 253alanine aminotransferase 39alanine dehydrogenase (ADH) 127aldose reductase activity 161alkylphosphocholine miltefosine 387allopurinol 9, 22, 23, 141allopurinol (4-hydroxypyrazolo(3,4-d)

    pyrimidine) 141alternative oxidase (AO) 123amastigotes 106aminobenzimidazole derivative 70aminoglycoside antibiotic paromomycin 18

    aminosidin. See paromomycinamino sugars catabolism 131amiodarone, as anti-parasitic agent 501, 5022-ammino-thiadiazole 466amphotericin B 9, 18, 387 deoxycholate 4 formulations 25 leishmanicidal properties 25 monomeric form 24 side-effect 25AM1 theory 63amyloidotic-type neurodegenerative

    diseases 154animal leishmaniases 19animal trypanosomiasis (Ngana) 515anti-Chagas therapy 290anti-fungal azoles 27anti-kinetoplastida drug design 5961anti-kinetoplastid agents 292anti-Leishmania antibody 20anti-leishmanial compounds 27antimonials, in combined therapy 26antimony-resistant Indian visceral

    leishmaniasis parasites 5antioxidant 356, 406 mechanisms 216 network 226anti-parasitic drugs 336anti-protozoan drugs 81anti-sleeping sickness drugs 366anti-trypanosomal compounds chemical structure, and biological

    activity 64anti-trypanosomal drugs 38, 387anti-trypanosomal hit/lead compounds

    58, 59anti-trypanosomal N-phenylpyrazole

    benzylidene-carbohydrazides 64apicoplast 336

    Trypanosomatid Diseases: Molecular Routes to Drug Discovery, First edition. Edited by T. Jger, O. Koch, and L. Floh.# 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

    j531

  • apoptosis 268273, 357 in protozoan parasites 268273 in trypanosomes 269, 270apoptosis-inducing factor (AIF) 269aquaglyceroporin (AQP2) 45arabinonolactone oxidase 132arginine decarboxylase (ADC) 175aromatic amino-methylene bisphosphonate

    derivatives 139aryl-quinuclidine derivatives 503ascorbate peroxidase 226ASINEX database 72Aspergillus fumigatus 481atazanavir 288ATGgenes 265ATG8 genes 267ATG8-lipidation pathway 267, 355Atg8 pathway 267ATP-competitive kinase inhibitors 291ATP-dependent DNA helicase 250auranon 239, 240AutoDock4 program 72autophagic pathway in Leishmania spp

    109, 354 ATG4 regulation 355, 356autophagolysosomal degradation 109autophagolysosomes 265, 268autophagosomes 267, 268, 352 ATG12ATG5 conjugation pathway, role in

    biogenesis and 358 biogenesis, molecular machinery for

    352, 355 degradation 355autophagy 135, 263, 352 Atg18Atg2 complex 264, 265 autophagic pathway in Leishmania spp 354 autophagosome formation 264, 265 Leishmanias cathepsins role in

    regulation 356358 regulation of induction 264, 265 in T. brucei 266 TORC complexes 265 vesicle nucleation 264autophagy-related proteins (Atg) 134, 265azoles 480 resistance 481

    bBacille Calmette-Guerin (BCG) 9Bayesian models 89, 90BaylisHillman chemistry 466B-cells 263BcrAbl kinase 291benznidazole 387, 467

    binding pocket prediction 75bioinformatics 267biomarkers 49N1,N8-bis(glutathionyl)spermidine.

    See trypanothione1,3-bisphosphoglycerate (1,3-PGA) 122bisphosphonates 140bloodbrain barrier (BBB) 45, 273bloodCSF barrier 271, 273B lymphocytes 497b-phenyl imidazoles 4996-bromo-5-methylindirubin-30-oxime 291buparvaquone 27L-buthionine-S,R-sulfoximine (BSO) 1732-[trans(4-t-butylcyclohexyl)-methyl]-3-hydroxy-

    1,4-naphthoquinone 27

    ccalpains 359Candida albicans 287candidate drug targets 141canine leishmaniasis, and chemotherapy

    1927 alkylphosphocholine 23, 24 allopurinol 22, 23 aminosidine 26, 27 amphotericin B 24, 25 drug delivery systems, use 25, 26 pentamidine 26, 27 anti-leishmanial drugs, exploration 27, 28 by Leishmania infantum 19, 20 pentavalent antimonials 2022cardiomyocytes 219caspases 358catalase 387cathepsin K inhibitors 288cathepsins 289, 290, 355 Kinetoplastid parasites producing 289 and virulence 356358CDD Database 83, 86 relevant trypanosomal disease screening

    datasets in 87 screenshot showing data mining

    facilities 89CD8 T cells 112cell antioxidant capacity 209cell death 261, 283central nervous system (CNS) 37central processing units (CPUs) 59cerebrospinal uid (CSF) 269, 273Chagas disease 57, 69, 81, 83, 122, 140, 141,

    215, 226, 386, 474, 476, 480, 490, 492, 501,505, 520. See also cruzain

    benznidazole 57

    532j Index

  • Centers for Disease Control and Prevention(CDC) estimation for 473, 474

    current therapy 474, 475 targetingT. cruzi protease cruzain 476, 477 CYP51 inhibitors 480 cysteine protease inhibitors, as

    chemotherapy for 477 drugs, for specic treatment 490493 EBIs as potential new therapeutic

    agents 493504 megasyndromes prevalence 474 mortality 474 new therapies for 473 nifurtimox 57 pharmacokinetics of K777 477 clinical trials and studies 477channel-forming proteins 142chemical ionization (CI) 41chemical libraries 61, 66, 68cheminformatics methods 83chemotherapeutic agents 18chinifur 419chloroquine resistance 343chloro-quinoline scaffold 64collaborative drug discovery (CDD)

    database 81, 86, 87 capability 88 screenshot showing data mining

    facilities 89, 90Combination therapies 5, 504, 505 aminosidine 26 benznidazole with ketoconazole 504 evaluation of efcacy 505 ketoconazole with alkyl-lysophospholipid

    analogs 504 nifurtimoxeornithine combination

    therapy 519 synergic effects 504compound libraries 143computational approaches, used for drug

    discovery 84, 85computational machine learning models 89computational protocol 74computer-aided drug design 58, 59contraception method 18Crithidia fasciculata 44, 181, 205, 243, 430cruzain 289 as good drug target 477, 478 potent inhibitors 478480 lack of correlation, protease inhibition and

    trypanocidal efcacy 480 non-peptidic cruzain inhibitors 479 pyridyl analog of K777 479

    toxicity 480cruzipaine 68cryptic infections 20CxxC-containing oxidoreductases 204CxxC-containing proteins 207cyclin-dependent kinases (CDKs) 291cyclodextrin-based formulations 46cycloguanil 467CYP51 activity, and sterol biosynthesis 4812-Cysperoxiredoxins (2-Cys-Prxs) 388Cys-protease motif 1762-Cys PRXs, mechanism of action 202, 203cysteine peptidases 352 downregulation in Leishmania spp. 352 inhibitors: opportunities and

    challenges 359, 360 dipeptidyl a-uorovinyl 359 a-ketoheterocyclics 359 metal-based inhibitors 359 vinyl sulfone inhibitor, K11777 359cysteine proteases 268 inhibitors 28, 288cysteines, overoxidation 180cytokines 7, 108, 215, 217, 266, 285, 325, 374cytokinesis 265cytosolic tryparedoxin peroxidase

    (cTXNPx) 217cytosolic TXN, downregulation 207cytotoxicity 62, 217, 374, 463, 465, 525

    ddata analysis 4244data mapping 88DDD85646 selectivity 288deglutathionylate proteins 180dehydroepiandrosterone (DHEA) 305dendritic cells (DCs) 106, 111, 112 dermal DCs 111 ICAM-3-grabbing non-integrin (DC-SIGN) 112 myeloid DCs (mDCs) 111 plasmacytoid DCs (pDCs) 111de novo synthesis compounds linking BTCP with diaryl

    sulde-based inhibitors 392 of Spd 173, 175 of sterols 495 of trypanothione 407density functional theory (DFT) level 63deoxyribonucleotides synthesis 18120-deoxythymidine-50-monophosphate

    (dTMP) 4462,4-diaminopyrimidines 4672,4-diaminoquinazolines 468

    Index j533

  • diaryl suldes 4201-(3,4-dichloro-benzyl)-2-amino-

    benzimidazole 4672,7-dichlorodihydrouorescein diacetate

    (DCFH2) 217diffusion 337339diuoromethylornithine (DFMO) 174, 387D,L-diuoromethyl ornithine (DFMO). See

    eornithinedihydrofolate reductase (DHFR) 46, 343,

    445, 446 crystallographic structures available from PDB 454 of TcDHFR-TS 454 folate analogs acting as DHFR

    inhibitors 446 inhibition of 467, 468 pathways involving 447 structural studies 453455 x-ray crystal structures 446dihydropteroate synthetase 343dihydroxyacetone phosphate (DHAP) 154diminazene aceturate resistance 343dinitrosyl-iron complex (DNIC) 178dipyridamole 283direct-squirt method 395,50-dithiobis(2-nitrobenzamide)

    (DTNBA) 407DNA-binding protein 247DNA degradation 269DNA fragments 45DNA helicases 246, 250, 251DNA polymerases 246, 249, 250, 257DNA primases 246, 248, 249DNA synthesis 182DNA TopoIImt 250DNA topoisomerases 244, 252, 253docking analysis 73docking-based binding mode 74 analysis 73dolichol-phosphate mannose synthase

    (DPMS) 318, 326, 327domperidone 27DpnII-PCR-RFLP 343, 344drug delivery systems, development 111drug design, and screening computer-aided drug design 58, 59 ligand-based approaches, against

    trypanosoma parasites 6165 molecular modeling, and anti-kinetoplastida

    drug design 5961 protein druggability, in silico

    prediction 7476 in silico approaches 5776

    structure-based drug design andscreening 6567

    workow 6567 supercomputers and other technical

    resources 59 virtual screening approaches against

    trypanosome proteins 6774drug discovery program 89druggability of target protein 74drug incubation Glossina infectivity test

    (DIGIT) 342drug incubation infectivity test (DIIT) 342drug mechanisms, biochemical

    investigation 48drug resistance 179, 180drug screening, for neglected disease 482 high-throughput assay 482 MTC assay and efcacy 483 quantitative method to test drug

    sensitivity 482 targeting ergosterol biosynthesis 480 in vitro drug screening 482drugs for neglected diseases initiative

    (DNDi) 475, 480, 499, 522drugs, for specic treatment of chagas

    disease 490. See also chagas disease benznidazole 490, 492, 493 ergosterol biosynthesis inhibitors

    (EBIs) 493 guidelines 493 limitations 490493 nifurtimox 490, 492, 493 2-nitromidazole 490

    eeornithine 47, 48, 387, 519eornithine (D,L-diuoromethyl ornithine

    (DFMO)) 47electronic descriptors 60EmbdenMeyerhof pathway 298endocytic pathway 111endocytosis 45, 266, 268, 288, 357endonuclease G 269endoplasmic reticulum (ER) 128, 316enolase (ENO) 122Entamoeba invadens 352enzyme-linked immunosorbent assay 19enzyme-mediated actions 179enzyme-selective inhibitors 141enzyme substitution mechanism 202epiandrosterone (EA) 305epimastigotes 128ergosterol biosynthesis inhibitors (EBIs)

    489, 493

    534j Index

  • Ergosterol synthesis 285Escherichia coli 41Euglena 405eukaryotic elongation factor 1B (eEF1B) 179exocytosis 266exponential-phase promastigotes 161

    fFansidar 343Farnesylation 285Fcc receptor-mediated phagocytosis 111ngerprint for ligands and proteins (FLAP) 76FK-binding protein 12, 264avin-disulde oxidoreductases 405avoenzyme TR 3875-formyl-6-hydroxy-2-naphthyl di-sodium

    phosphate 139Fourier transform ion cyclotron resonance

    (FT-ICR) mass spectrometers 41FRED program 72fructose-1,6-bisphosphatase (FBPase) 131fructose-6-phosphate 138, 317fumarate hydratase (FH) 127functional genomics projects 143

    gGDP-mannose, biosynthesis and

    consumption 316GDP mannose dehydratase (GMD) 138GDP-mannose-dependent

    mannosyltransferases 316, 327GDP-mannose pyrophosphorylase

    (GDP-MP) 125, 317GDP-mannose transporter (LPG2) 327, 328gene expression proles 157c-glutamylcysteine synthetase (GSH1) 387GLO1-encoding gene 155GLO1green uorescent protein

    construct 158glomerular ltration rate 23glucantime 21gluconeogenesis 130, 298gluconeogenic enzymes 131glucosamine-6-phosphate N-acetyltransferase

    (GNA) 138glucose based metabolism, of trypanosomatids

    39, 298 consumption 271glucose-6-phosphate (G6P) 130, 298glucose-6-phosphate dehydrogenase

    (G6PDH) 46, 125, 178, 298glucose transporter 124, 125

    c-glutamylcysteine synthetase (GshA) 46, 173glutaredoxins 388glutathione (GSH) 336, 429 functional replacement 153glutathione peroxidase (GPX) 201, 225, 254glutathione reductase (GR) 387 protein backbone for human GR(hGR) 410glutathione synthetase 173, 388glutathionylspermidines 406glutathionyl spermidine synthetase

    (GspS) 175, 430glyceraldehyde-3-phosphate (Gly3P) 154, 298glyceraldehyde-3-phosphate dehydrogenase

    (GAPDH) 122glycerol kinase (GK) 124glycerol-3-phosphate/DHAP shuttle 158glycerol-3-phosphate oxidase (GPO)

    system 123glycine 267, 355glycoconjugates 316 mannosylation 317glycogen synthase kinase-3 (GSK-3) 291glycolipids 315glycolysis 21, 43, 128, 141, 262, 298 in trypanosomes 263glycolytic enzymes 127, 262 in cell-free assays 46glycolytic ux 125, 133, 160glycolytic pathway 130, 298glycosomal enzymes 141 kinetic properties 127glycosomal membrane 133 controlled communication across 132134glycosomal NADH-dependent glycerol-3-

    phosphate dehydrogenase (G3PDH) 123glycosomal solute transporters 142glycosomal targeting signal 204glycosomes 121, 262, 298 inhibitors of glycosomal enzymes/

    processes 138141 integration of glycosomal metabolism relation to life cycle differentiation

    134, 135 potential drug targets 136, 137 target characterization, achievements

    135, 138glycosylation, eukaryotic 315glycosylinositolphospholipids (GIPLs) 317glycosylphosphatidylinositol (GPI) 315glyoxalase enzymes glyoxalase I 155157 glyoxalase II 157, 158 glyoxalase pathway 153155

    Index j535

  • regulation 158160 as therapeutic target 160162 in trypanosomatids 153163glyoxalase pathway 153155, 161 regulation 158160 as therapeutic target 160162glyoxalase system, in trypanosomatids 154GOLD docking program 72GPXs three-dimensional structure 206GPx-type peroxidases 182, 184, 185graphic processing units (GPUs) 59graphic user interface (GUI) 87GRID force eld parameterization 76GTPase Ras-related protein (Rab) 112guanosine-diphospho-D-mannose

    pyrophosphorylase (GDP-MP) 325, 326guide RNA (gRNA) molecules 244

    hHAT. See human African trypanosomiasis

    (HAT)HeLa cells 184helper T (Th) cells 216hemolymphatic system 37hetero-oligomers 139hexadecylphosphocholine 23hexokinase 122, 317, 322, 323 crystallographic analysis 322 inhibitors 139, 322 isozymes 322hexose transporter 130, 318, 322HGPRT ligands 141high-afnity pentamidine transporter

    (HAPT1) 44high-throughput screening (HTS)

    technologies 67, 82, 138, 177, 184histone H1-like proteins 248H2O2-induced programmed cell death 208homeostasis 352homologous protein 60homology modeling docking crystal structure of TbAtg8 to Atg4 from rat 267homolysis 219host cells, of Leishmania 106111host-nitrated proteins 219hosts defense mechanisms 167hosts oxidative defense 135HTS Data for machine learning models

    8998HTS repurposing molecules, for trypanosomal

    diseases 82human African trypanosomiasis (HAT) 37,

    365, 515 current chemotherapeutic agents for 518

    eornithine (ornidyl,diuoromethylornithine) 519

    melarsoprol 517, 518 nifurtimoxeornithine combination

    therapy 519 pentamidine 518, 519 philanthropic support from

    foundations 520 suramin 518 DFMO treatment 174 life cycle of trypanosome 516, 517 new trypanocidal agents 520 benzoxaboroles 522526 diamidines 521 fexinidazole 520, 521 nitroimidazoles 520human glutathione reductase (hGR)...

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