Index

aacidocalcisomes 266activated protein-1 (AP-1)– component 109active ligands 59active-site cysteine residue 183active smallmolecules, chemical structure 57adenosine ribose 139a-difluoromethylornithine (eflornithine) 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 59–61anti-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. Jäger, O. Koch, and L. Flohé.# 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

j531

apoptosis 268–273, 357– in protozoan parasites 268–273– 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 250auranofin 239, 240AutoDock4 program 72autophagic pathway in Leishmania spp

109, 354– ATG4 regulation 355, 356autophagolysosomal degradation 109autophagolysosomes 265, 268autophagosomes 267, 268, 352– ATG12–ATG5 conjugation pathway, role in

biogenesis and 358– biogenesis, molecular machinery for

352, 355– degradation 355autophagy 135, 263, 352– Atg18–Atg2 complex 264, 265– autophagic pathway in Leishmania spp 354– autophagosome formation 264, 265– Leishmania’s cathepsins role in

regulation 356–358– 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, 90Baylis–Hillman chemistry 466B-cells 263Bcr–Abl kinase 291benznidazole 387, 467

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

See trypanothione1,3-bisphosphoglycerate (1,3-PGA) 122bisphosphonates 140blood–brain barrier (BBB) 45, 273blood–CSF 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

19–27– 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 20–22cardiomyocytes 219caspases 358catalase 387cathepsin K inhibitors 288cathepsins 289, 290, 355– Kinetoplastid parasites producing 289– and virulence 356–358CDD Database 83, 86– relevant trypanosomal disease screening

datasets in 87– screenshot showing data mining

facilities 89CD8þ T cells 112cell antioxidant capacity 209cell death 261, 283central nervous system (CNS) 37central processing units (CPUs) 59cerebrospinal fluid (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 specific treatment 490–493– EBIs as potential new therapeutic

agents 493–504– 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 efficacy 505– ketoconazole with alkyl-lysophospholipid

analogs 504– nifurtimox–eflornithine 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 478–480– – lack of correlation, protease inhibition and

trypanocidal efficacy 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-fluorovinyl 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 42–44data 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

sulfide-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 sulfides 4201-(3,4-dichloro-benzyl)-2-amino-

benzimidazole 4672,7-dichlorodihydrofluorescein diacetate

(DCFH2) 217diffusion 337–339difluoromethylornithine (DFMO) 174, 387D,L-difluoromethyl ornithine (DFMO). See

eflornithinedihydrofolate 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 453–455– x-ray crystal structures 446dihydropteroate synthetase 343dihydroxyacetone phosphate (DHAP) 154diminazene aceturate resistance 343dinitrosyl-iron complex (DNIC) 178dipyridamole 283“direct-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 61–65– molecular modeling, and anti-kinetoplastida

drug design 59–61– protein druggability, in silico

prediction 74–76– in silico approaches 57–76

– structure-based drug design andscreening 65–67

– – workflow 65–67– supercomputers and other technical

resources 59– virtual screening approaches against

trypanosome proteins 67–74drug 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 efficacy 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 specific treatment of chagas

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

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

eeflornithine 47, 48, 387, 519eflornithine (D,L-difluoromethyl ornithine

(DFMO)) 47electronic descriptors 60Embden–Meyerhof 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 111fingerprint for ligands and proteins (FLAP) 76FK-binding protein 12, 264flavin-disulfide oxidoreductases 405flavoenzyme 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 profiles 157c-glutamylcysteine synthetase (GSH1) 387GLO1-encoding gene 155GLO1–green fluorescent protein

construct 158glomerular filtration 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 flux 125, 133, 160glycolytic pathway 130, 298glycosomal enzymes 141– kinetic properties 127glycosomal membrane 133– controlled communication across 132–134glycosomal NADH-dependent glycerol-3-

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

processes 138–141– 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 155–157– glyoxalase II 157, 158– glyoxalase pathway 153–155

Index j535

– – regulation 158–160– – as therapeutic target 160–162– in trypanosomatids 153–163glyoxalase pathway 153–155, 161– regulation 158–160– as therapeutic target 160–162glyoxalase 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 field 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-affinity 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 106–111host-nitrated proteins 219host’s defense mechanisms 167host’s oxidative defense 135HTS Data for machine learning models

89–98HTS repurposing molecules, for trypanosomal

diseases 82human African trypanosomiasis (HAT) 37,

365, 515– current chemotherapeutic agents for 518

– – eflornithine (ornidyl,difluoromethylornithine) 519

– – melarsoprol 517, 518– – nifurtimox–eflornithine 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 522–526– – diamidines 521– – fexinidazole 520, 521– – nitroimidazoles 520human glutathione reductase (hGR) 71human leishmaniasis 17human parasitic trypanosomatid species,

glycosomal enzymes 142Hybrid compounds, with a dual mechanism

of action 503, 504hydrogen bond 224, 336, 337, 393, 448,

452, 465hydrolytic enzymes 352hydroperoxide metabolism 181, 182hydroperoxide-reducing enzymes 201, 207hydroperoxides– broad spectrum 201– TXN/TXN dependent Prx (TXNPx)-mediated

removal 179hydrophilic interaction chromatography

(HILIC) 41hydrophobic interaction 4661-(3-(4-hydroxybutoxy)-4-methoxyphenyl)-3-

methylbutan-1-one 283hypoglycemic shock 262hypoxanthine 22hypoxanthine-guanine

phosphoribosyltransferase (HGPRT) 129

iIDN-6556 288IFATtest 23immune evasion strategies 112immunomodulating molecules 106immuno-stimulated macrophages 217indirect fluorescent antibody test (IFAT) 19inducible nitric oxide synthase (iNOS)

108, 215inhibitors targeting, conserved proteins 284inorganic pyrophosphate (PPi) 127, 129in silico structure-based approaches 58,

60, 70

536j Index

in silico two-dimensional (2-D) bond basedlinear indices 62

in silico virtual screening approaches 71intellectual property (IP) arrangements 83inter alia proteins 184interferon (IFN)-c 8, 217interferon (IFN)-c–inducible protein

(IP)-10 107interleukin-2 263intraglycosomal inorganic pyrophosphate

(PPi) 129in vitro fluorimetric assays 69iron–sulfur cluster (ISC) metabolism 168,

178, 179isoprenoids 129itraconazole 481

jJanus kinase/signal transducer and activator of

transcription (JAK/STAT) 108

kkala-azar 25, 386, 405KAP3 and KAP4 proteins 248kDNA chain elongation 249kDNA repair enzymes 251kDNA replication 244, 249, 251– genes, periodic expression 254, 255– machinery as an anti-trypanosomal drug

target 256, 257– machinery, components 247– model 245– proteins 253– regulation 253, 255– – replication initiation 253, 254– – role of mitochondrial HslVU

protease 255– replication proteins, and complexes 247– role of DNA topoisomerases 252– topological reactions during 252kinases 290–292– inhibitors 292kinetoplast-associated proteins

(KAPs) 243kinetoplast DNA (kDNA) 243kinetoplast DNA helicases 250kinetoplastida 238, 266– drug targets 74kinetoplastid selenoproteome 238, 239kinetoplasts 248Krebs cycle 21Kyoto Encyclopedia of Genes and Genomes

(KEGG) 43

llactaldehyde dehydrogenase system 158S-D-lactoyltrypanothione 155Langerhans cells (LCs) 111Laplacian-corrected Bayesian classifier

models 89Leishmania amastigotes 130, 135Leishmania amazonensis 108, 109– MAPK/ERK pathway in 112Leishmania braziliensis 107, 208Leishmania chagasi 17, 19, 207Leishmania chemotactic factor (LCF) 107Leishmania donovani 3, 18, 107, 405, 430– proliferation 177Leishmania–host cell relationships 105Leishmania infantum 3, 18, 19, 153, 205, 430– detoxification enzymes 160– glyoxalase II, trypanothione specificity

in 159– infections by 19– methylglyoxal metabolism in 161– progressive reduction 24– resistant strains 26Leishmania-infected macrophages 108Leishmania major 282, 317, 352, 430– GDP-mannose 317– glucokinases 323– TryS crystal structure 176Leishmania mexicana 18, 327, 352– Dlpg2 mutants 327Leishmania parasites– dendritic cells (DCs) 111, 112– glycosomes 130–132– host cells 106–111– interaction with host cells functional

consequences 105–113– life cycle 105, 106– macrophages 107–111– neutrophils 106, 107– non-essential enzyme in 208– promastigotes– – phagocytosis 110, 111– TXNPx 180leishmaniasis 297, 351– chemotherapy 17–28, 386– – canine leishmaniasis 19–27– – status 17, 18– muco-cutaneous leishmaniasis

(espundia) 386– visceral leishmaniasis 386Leishmania tarentolae 243Leishmania tropica 405leishmanicidal compounds 110

Index j537

ligand-based approaches 60, 61, 63– against trypanosoma parasites 61–65ligand binding sites 76ligand–protein interactions 67ligand similarity filter 71LIG ka protein 252LIG kb expression 252linear discriminant analysis (LDA) 61Lipinski’s rule 69lipoamide dehydrogenase (LipDH) 406, 409lipophilic hydroperoxides 201lipophilic pockets 75lipophosphoglycans (LPGs) 111, 317liposomal amphotericin B 4, 8– single-dose treatment 5low-affinity pentamidine transporter

(LAPT1) 44low-cost drug delivery system 26lowest unoccupied molecular orbital

(LUMO) 64LP10 inhibitor 481lysosomal hydrolases 111, 265lysosomes 336, 352lysosomotropism 289

mmachine learning models 99macroautophagy 352macromolecules synthesis 174macrophage inflammatory protein

(MIP)-1b 107macrophages 107–111, 218, 356– functions, manipulation 107–110– parasitophorous vacuoles in 110, 111major histocompatibility complex (MHC)

class II 108malate dehydrogenase (MDH) 127mammalian target of rapamycin (mTOR) 108– proteolytical cleavage 109mammals vs kinetoplastids– enzymes and transporters involved in

mannosylation 318–322– – dolichol-phosphate mannose synthase

(DPMS) 326, 327– – GDP-mannose-dependent

mannosyltransferases 327– – GDP-mannose transporter 327, 328– – guanosine-diphospho-D-mannose

pyrophosphorylase (GDP-MP) 325, 326– – hexokinase 322, 323– – hexose transporter 318, 322– –mannosylphosphatetransferases(MPTs) 328– – phosphoglucose isomerase (PGI)

323, 324

– – phosphomannomutase (PMM) 324, 325– – phosphomannose isomerase (PMI) 324– mannosylation pathways 317, 318mannogen synthesis 131mannose-1-phosphate (M1P) 317mannose-6-phosphate (M6P) 317mannosylation pathways– mammals vs kinetoplastids 317, 318mannosylphosphate transferases (MPTs) 318,

328matrix proteins 134meglumine antimoniate 20, 22, 387melarsen oxide–trypanothione conjugate

(MelT) 46melarsen–trypanothione adduct (MelT) 47melarsoprol 46, 47, 387, 517, 518melarsoprol–DFMO combined therapy 174metabolite translocation 134metabolomics 37, 407– new technologies applied to

Trypanosomes 38–44– – data analysis 42–44– – MS-based metabolomics 40–42– – NMR-based metabolomics 39, 40– – sample preparation 38– potential role 49metacaspases (MCAs) 269, 357metacyclic promastigotes 106methemoglobinemia 418methionine sulfoxide reductase (MSR)

183, 388– nucleophilic cysteine 183methylene blue 418– redox cycles 419methylglyoxal 179– catabolizing enzymes 160– formation system 158– metabolism 160– pathway 153– steady-state concentration 161methylglyoxal (MG) metabolism– sensitivity analysis 162methylthioadenosine phosphorylase 184mevalonate kinase (MK) 131Microsoft Excel-based application 43MIF-like proteins 110migration inhibitory factor (MIF)-like

proteins 110miltefosine 9, 23, 24, 358– dog leishmaniasis treatment 23– limitation 24– pharmacokinetic profile 5– in visceral leishmaniasis treatment 3mitochondrial DNA ligases 251, 252

538j Index

mitochondrial DNA primases 255mitochondrial DNA replication 183mitochondrial DNA TopoIImt 246mitochondrial HslVU protease 255mitochondrial outer membrane

permeabilization (MOMP) 357mitogen-activated protein kinase (MAPK)

pathways 108MM-GBSA approaches 66molecular mechanics (MM) methods 58molecular modeling 59–61mononuclear phagocytic cells 107mononuclear phagocytic system 19MS-based metabolomics 40–42– GC-MS-based metabolomics 40, 41– LC-MS-based metabolomics 41, 42multidrug treatment regimens, advantage 7multiple reaction monitoring (MRM)

approaches 42mutations 343– indicative G!A point mutation 343– PfCRT1 343– point mutation in TcoAT1 343– resistance-associated (“mutated”) TcoAT1

allele 343

nN-acetylcysteine 356NAD-dependent fumarate reductase

(FRD) 127NAD(P)-dependent lactaldehyde

dehydrogenase 179NADPH-dependent aldose reductase 160NADPH-dependent disulfide reductases 406NADPH-dependent flavoenzyme TR, in

kinetoplastid parasites 406NADPH-dependent glutathione/GR

system 406NADPH-dependent methylglyoxal

reductase 158NADPH-dependent trypanothione

reductase 167NADPH oxidase 215Nagana cattle disease 405naphthoquinone (NQ) derivative 27, 409– derived from menadione, plumbagin, and

juglone, structures 412– 1,4-NQs as trypanocidal agents 409–413– oxidoreduction 409– structures of trypanocidal 1,4-NQs– – acting as subversive substrates 411natural killer (NK) cells 107, 216necrosis 261

neglected diseases 105neglected tropical diseases (NTDs) 3, 386network-based representations 43neutrophils 106, 107new anti-leishmanial drugs, exploration

of 27, 28new chemical entity (NCE) 10N-glycosylated proteins 315Ni2þ-dependent proteins 156nifurtimox 48, 61, 387, 413nifurtimox–eflornithine combination therapy

(NECT) 44, 48, 387nifurtimox-resistant 289nitric oxide (�NO) 178, 216nitrofurans 413, 473– anti-trypanosomal drugs– – development events 413– – nitrofurazone 416– – prodrug NFOH-121 416– – recently developed, with anti-parasitic

activity 416– – synthesis of hydroxymethylnitrofurazone

from 416– derivative 409– parasitic targets, and mechanism

of action 414, 415– redox cycle in presence of molecular

oxygen 415– toxicity 413nitrofurazone 416nitroimidazoles 413NMR-based metabolomics 39, 40N-myristoyltransferase (NMT) 287, 288– inhibition and trypanocidal activity 288non-folate-related DHFR inhibitors 468non-homologous enzymes 135non-ionic surfactant vesicles 22NOS isoforms 218Noxafil1 480, 496nsGPXs, mechanism of action 202, 203nuclear factor “kappa light chain enhancer” of

activated B cells (NF-kB) 110nuclear magnetic resonance (NMR) 38, 60– Bringaud’s systematic application 40nucleic acids, as chemical building blocks 38nucleoprotein complex 254

oodanacatib 288ODC expression 47Okazaki fragments 245, 252oligosaccharide mannogen 131open-access chemistry databases 83

Index j539

Oriental sore 405origin recognition complexes (ORCs) 253ornithine decarboxylase (ODC) 46, 47, 174,

292, 387orotidine-50-monophosphate

decarboxylase 132orphan drug 18osteoporosis 288oxidative stress 407oxidoreductase tryparedoxin (TXN) 168oxidosqualene cyclase (lanosterol synthase)

inhibitors 501, 5022-oxoaldehyde 153oxygen metabolites 106

pparallel artificial membrane permeation assay

(PAMPA) 337parasitemia 271parasite persistence mechanisms 8parasite’s redox homeostasis 177parasite target-oriented compounds 18parasitophorous vacuoles (PVs) 105, 106paromomycin 18, 26, 27, 387– non-inferiority 5– in visceral leishmaniasis treatment 3part fatal diseases 17pathogen–host cell interactions 113PC-based database systems 86PDSP dataset 88pentamidine 44, 45, 518, 519pentamidine dimetasulfonate 27pentamidine isethionate 26pentavalent antimonials 20pentose-phosphate pathways (PPP) 122, 128,

135, 298, 300, 301– enzymes, from trypanosomatids 125, 129,

303–305– inhibitor discovery against enzymes

305–308pentose phosphate shunt 178PEP carboxykinase (PEPCK) 127peptidases 352– Clan CA peptidases, with roles in

ubiquitination 358– mitochondrion ubiquitin-like peptidase

(MUP) 359– potential peptidase targets in Leishmania

spp. 353peptide-based drugs, drawbacks 290peptidic substrate 184peptidomimetic K777 476peroxidases 217– as drug targets 184, 185

peroxidatic cysteine 202, 205peroxins (PEXs) 121, 134peroxiredoxin (PRX) 201peroxisomal enzymes 122peroxisomal membranes 133peroxisome-targeting signal (PTS) 128peroxynitrite anion (ONOO–) 216peroxynitrite detoxification systems 222–226peroxynitrite diffusion 219–222peroxynitrite formation– in immuno-stimulated-infected

macrophages 218– during T. cruzi–mammalian host cell

interaction 216peroxynitrite reactivity with T. cruzi

targets 219–222peroxynitrite reduction kinetics 225peroxynitrous acid (ONOOH) 216PEX proteins 142P38 gene 248PGK reaction 124phagophore 263, 3554-phenoxyphenoxyethylthiocyanate

(WC-9) 1401-phenyl-4-glycosyl-dihydropyridines 465phosphatidylethanolamine (PE) 265, 355phosphatidylinositol-3 kinase (PI3K)

pathway 108phosphatidylinositol-3-phosphate 2655-phosphoarabinonohydroxamic acid

(5PAH) 324phosphodiesterases (PDEs) 282– inhibitors 282, 283phosphoenolpyruvate (PEP) 127phosphofructokinase (PFK) reactions 1226-phosphogluconate dehydrogenase

(6PGDH) 125, 2986-phosphogluconolactonase (6PGL) 298phosphoglucose isomerase (PGI) 317, 323,

324– expression products encoded by 3236-phosphoglunocolactone

dehydrogenase 1783-phosphoglycerate (3-PGA) 122phosphoglycerate kinase (PGK) 44, 122phosphoglycerate mutase (PGAM) 122phosphoinositide 3-kinase (PI3K) 291phospholipid bilaminar complexes 25phospholipids 352phosphomannomutase (PMM) 317, 324, 325phosphomannose isomerase (PMI) 317, 324– deficiency 324– leishmanial and trypanosomal 324phosphorylated hexoses 128

540j Index

phosphoseryl-tRNA kinase (PSTK) 239piperidine derivative 71plant peroxisomes 133plasma membrane hexose transporter 128Plasmodium falciparum 156, 182, 392, 405– glutathione reductase (GR) schematic

presentation 407pleiotropism 185Pneumocystis carinii 26PocketPicker 75polar replication model 247polyamines 47, 48, 388– deficient media 174– production 174polycyclic compound 71polymerase chain reaction (PCR) 19posaconazole 286, 480, 481, 496–498– efficacy 481post-kala-azar dermal leishmaniasis

(PKDL) 3, 4, 8–10– Leishmania donovani 8– Leishmania infantum 8– pathology and immunopathology 8, 9– susceptibility 9– treatment options for 9, 10potential resistance mechanisms 49PPi-susceptible glycosomal enzymes 140PPP enzymes 125, 140pre-autophagosomal structure (PAS) 263PRI1 gene 249procyclic-form trypanosomes 125procyclic promastigotes 106procyclic trypanosomes 39pro-inflammatory cytokines 109prolactin production 27proof-of-concept 7– study 49propidium iodide 261prostaglandin (PG) D2 (PGD2) 269– applications 269proteases 288– cellular functions 370– – proteasome 373– – TbCALPs 371– – TbCATB and TbCATL 370– – TbGPI8 372– –TbMCA2,TbMCA3,andTbMCA5 371,372– – TbMSP-B 373– – TbOPB and TbPOP 372– as drug targets 373– – proteasome 377, 378– – TbCALPs 374– – TbCATB and TbCATL 373, 374

– – TbGPI8 374, 375– – TbMCAs 374– – TbMSP-B 377– – TbOPB and TbPOP 375, 376– inhibitors 288Protein Data Bank 393Protein Data Bank (PDB) 60, 393protein druggability, in silico prediction

74–76protein farnesyltransferase (PFT) 285, 499protein–ligand complexes 66, 399protein–protein interactions 76protein structures, x-ray resolution 67protein tyrosine phosphatase (PTP) 108proteolytical modification, of transcription

factors 109proteomic analysis 47proteophosphoglycans (PPGs) 317protozoan parasites 282protozoan transporters, selective uptake

by 339–341Pseudomonas aeruginosa 156Pseudomonas putida 156pteridine reductase (PTR1) 445, 446– crystallographic structures, available in

PDB 450– from DHFR to PTR1 Inhibitors 465, 466– – docking studies on compounds 465– discovery and development of

inhibitors 455– – chemical structures and activity

values 456–464– – compounds with similar structures 455– – 5-deazapteridines 455– – diaminopteridines 455– – pteridine-like compounds 455, 465– – quinazolines 455– LmPTR1 structure 451– non-pteridine-like PTR1 inhibitors 466, 467– pathways involving 447– promising drug targe 446– residues forming LmPTR1 active site 451– structural studies 446, 448, 451–453– in trypanosomatidic parasites– – alignment of PTR1 sequences 449– – identity (and similarity) among PTR1

sequences 448– x-ray crystal structures 446purine metabolism 23purine salvage 298PYK isoenzymes 138pyridine-indomethacin amide derivative

LP-10 500

Index j541

pyrimidine biogenesis 298pyruvate kinase (PYK) 122pyruvate phosphate dikinase (PPDK) 127

qQM methods 63QM simulations 58quantitative statistical models 74quantitative structure–activity relationship

(QSAR) 61, 62, 64, 83quantum mechanics (QM) methods 58quinols 423, 424– proposed mode of action 424quinones 409

rRadanil1 387rapamycin 263, 264, 267rapid filtration method 39ravuconazole 286reactive oxygen species (ROS) 271receiver operating characteristic (ROC)

value 90recombinant enzyme 140recombinant proteins 183recombinant TbPIF5 DNA helicase 250recombinant TbPIF1 protein 250redoxin and DNA synthesis 182, 183, 184redoxin-dependent enzymes 183redoxin-dependent functions 180, 181redoxin-independent functions 178redoxins 184– as drug targets 184, 185redox metabolism 182redox sensors 168relacatib 288ribonucleotide reductase (RnR) 182, 388ribose-5-phosphate (R5P) 298ribose-5-phosphate isomerase (RPI) 298– from trypanosomatids 304ribosomes 265ribulose-5-phosphate epimerase (RPE) 298RITSeq approach 45, 47, 48RNA interference (RNAi) 124, 168, 207, 281– analysis 247– drug targets by 135– mediated downregulation 173– pathway 45roflumilast 283

sSaccharomyces cerevisiae 156S-adenosylmethionine decarboxylase

(SAMDC) 44

salicylhydroxamic acid (SHAM) 124sample preparation 38, 39saquinavir 288Schizosaccharomyces pombe 183scoring function 66screening approaches towards TR 391– combined in vitro/in silico screening

campaign 393– – workflow 394– consensus pharmacophore building

398, 399– – by docking and clustering

experiments 399– – DrugscoreMaps approach 398– – kinetic analysis 398– current state of the art 391–393– second in vitro screen 397, 398– in silico screening 396, 397– TR assay adaptation 395– in vitro screening 395, 396Sec insertion sequence (SECIS) element 238SECISearch 238SecS genes 239, 240selenocysteine (Sec) 237selenocysteine-containing glutathione

peroxidases (GPXs) 181, 387selenoproteome 239, 240– default pattern of SECISearch 238– dispensable 239, 240– of kinetoplastids 239– relevant for long-term protection 240short-coursemultidrug treatment regimes 5signal-to-noise ratios 82single-dose liposomal amphotericin B plus

miltefosine 7site-directed mutagenesis 202sleeping sickness 272, 365, 385, 386– chemotherapy 366sodium stibogluconate 4, 21, 387spermidine 48, 387, 388, 430spermidine-interacting residues 158spermidine synthase (SpdS) 175, 388squalene synthase (SQS) 129, 140squalene synthase inhibitors 502, 503Sterol C14a-demethylase (CYP51) 489– inhibitors 495–501sterols 493stoichiometry-based models 43Streptomyces hygroscopicus 263Streptomyces nodosus 24structure–activity relationship (SAR)

analysis 62, 83, 135structure-based approaches 66, 68– requirement for 65

542j Index

structure-based docking 73structure-based drug design, and

screening 65–67structure-based pharmacophore models 66,

72, 75structure-based virtual screening 65, 71structure-specific endonuclease 1 (SSE1) 246substrate-binding pocket 185sugar nucleotides 125supercomputers 59superoxide radical 215suramin 45, 46, 518

tTAC proteins p166 247target of rapamycin (TOR) 291target protein 74target receptor 60, 75– 3-D structure 59Tau protein 418TbGPXA2– crystal structure 206TbHslVU protease 250TbPDEB1 inhibitor 283TbPIF5 allele 250– overexpression 251TbPIF1 and TbPIF2 DNA helicase 250TB project 86TCA cycle 127T-cell receptor genes 476T-cells 263TcoAT1 resistance allele 344teratogenicity 351tetrafluoromethyl ketones 479tetrahydrophthalazinone 283thiol-dependent reactions 167thiol–disulfide exchange 202thiol/disulfide oxidoreductases 180thiol group 352thiol peroxidases– function in trypanosomatids 207–209– mechanism of reaction 202–204– thiol-dependent peroxidases in

trypanosomatids 201, 202– trypanosomatid GPXs 205–207– trypanosomatid PRXs 204, 205– of trypanosomatids 201–209thioredoxin homolog “tryparedoxin”

(TXN) 429thioredoxin recognition 207thioredoxin reductase (TrxR) 387thioredoxins 204, 388thioredoxin/TrxR system 406

thymidylate synthase (TS) 445, 446time-of-flight (TOF) 41tipifarnib 499– analog 500a-tocopherol– water-soluble version 182TOF detectors 42topological molecular computer design

(TOMOCOMD) approach 61–63TORC complexes 265TOR complex 1 (TORC1) 264TOR kinases 265TOR-like proteins 265Toxoplasma gondii 185, 352track sugar nucleotide 42transaldolase (TAL) 298transcription factor 183transferrin 268transforming growth factor (TGF)-b 107transketolase 298transporters– protozoan transporters, selective uptake

by 339–341– role of efflux transporters 341, 3421,2,3-triazole-based tetrafluoromethyl

ketone 479triazole derivatives, chemical structures 496– ravuconazole 496, 498– TAK-187 496, 498– UR-9825 496, 498tricarboxylic acid (TCA) cycle 40– enzymes 122Trichomonas vaginalis 336tricyclic system 72trimethoprim 4672,2,4-trimethyl-1,2-dihydroquinolines

(THQs) 417, 418– with anti-trypanosomal activities 417– anti-trypanosomal mechanism of 418– in vitro anti-trypanosomal structure–activity

relationship 417TR inhibitors 72triosephosphate isomerase (TPI) 124triostam 387tripartite attachment complex (TAC) 247triple-quadrupole mass spectrometers 42TriTryp genomes 173trypanocidal drugs– mode of action 38trypanocidal drugs, metabolic affects

44–48– eflornithine 47, 48– melarsoprol 46, 47

Index j543

– NECT 48– pentamidine 44, 45– suramin 45, 46Trypanosoma brucei 37, 81, 122, 153, 157, 336,

352, 429– cathepsins 290– cell density regulation in 272– cellular functions of proteases 370–373– classes of proteases 366– – calpain-like proteins 368– – cathepsin B- and L-like proteases 366– – cysteine peptidases 366– – GPI : protein transamidase 368, 369– – metacaspases 368– – metalloproteases 369, 370– – serine peptidases 369– – threonine proteases 370– etiological agent of HAT 365– genome 43– GLO1 enzyme in 161– glycosomes 122–125– hexokinases 323– infection 40– lipidomic analysis 42– PDEBs as drug targets 284– PEX proteins 134– 6PGDH 304– procyclic forms 39– proteases, as drug targets 373–378– pteridine reductase 1 (PTR1) 69, 70– resistance against diamidine

compounds 343– statistics on X-ray resolution of protein

structures 67– subspecies, disease patterns caused by 365– – gambiense 365– – rhodesiense 365– UCSF dataset 95–98Trypanosoma brucei gambiense 41, 405– life cycle 516, 517– polyamine biosynthesis in 48Trypanosoma brucei pteridine reductase 1

(PTR1) 69, 70Trypanosoma brucei rhodesiense 37, 405Trypanosoma brucei St Jude’s dataset 91–94Trypanosoma congolense 405Trypanosoma cruzi 215, 352, 405, 430– antioxidant enzymes, as virulence

mediators 226–228– antioxidant network 226– chemical structure and biological

activity 62, 64– – discovered by using the in silico-based

technique 62

– competitive inhibitors 68– cruzain activity 478– cruzain identified by means of virtual

screening 68– crystal structure of CYP51 complexed with

posaconazole 497– dihydrofolate reductase (DHFR) 69– – chemical structure and inhibitory

activity 70– – function 70– DNA primase 1 (TbPRI1) 216– epimastigote forms 61– glucokinases 322, 323– glycosomes 125–130– inhibitory activity of TcTS inhibitor 69– killing by intraphagosomal peroxynitrite

and 227– lead compounds, inhibiting enzymatic

targets 481– mammalian host cell interaction 216–219– nitrofurazone, reduced by LipDH 416– peroxynitrite formation during mammalian

host cell interaction 216– PIF1-like proteins 251– PRI1 gene 255– resistant to current therapy 481, 482– SPS2 240– statistics on the X-ray resolution of protein

structures 67– sterols 494– – structure and function of 493–495– TR inhibitor– – chemical structure and inhibitory

activity 72– trypanothione reductase (TR) 70–74– – protein backbone 410– – schematic presentation 407Trypanosoma cruzi trans-sialidase (TcTS)– chemical structure and inhibitory

activity 69Trypanosoma evansi 44trypanosomal diseases 99– CDD database 83–89– computational approaches and collaborative

drug discovery 81–99– drug discovery, computational approaches

for 84, 85– HTS repurposing molecules for 82– machine learning models, using HTS data

for 89–98– screening datasets 87trypanosomal proteasome 370, 373, 378trypanosomatids 141, 246– carbonyl and redox stresses in 163

544j Index

– Chagas disease (See Chagas disease)– function of thiol peroxidases 207–209– glyoxalase enzymes 153–163– – connection between carbonyl and redox

stresses 163– – glyoxalase I 155–157– – glyoxalase II 157, 158– – glyoxalase pathway 153–155– – glyoxalase pathway as a therapeutic

target 160–162– – glyoxalase pathway regulation 158–160– glyoxalases– – X-ray crystallographic structures 156– glyoxylase system 178– GPXs 205–207– hydroperoxide elimination in 201– hydroperoxide-reducing enzymes 209– major metabolic pathways/parts of pathways

found in 123– mechanism of reaction of thiol

peroxidases 202–204– metabolism– – controlled communication essentiality

across glycosomal membrane 132–134– – correct integration essentiality of

glycosomal metabolism in 134, 135– – glycosomal enzymes/processes, inhibitors

development 138–141– – glycosomal metabolism pathway, diagram

presenting enzymes 123– – glycosomes function and glycosomal

proteins as drug targets 121–143– – Leishmania spp., glycosomes 130–132– – metabolic processes, enzymes presents

in 126– – target characterization 135–138– – T. brucei, glycosomes 122–125– – T. cruzi, glycosomes 125–130– Nagana (Surra) cattle disease 386– nsGPXs 206– oxoaldehyde metabolism 179– parasitic diseases caused by 385, 386– pathogenic 121– potentialdrug targets inglycosomes 136,137– PRXs 204, 205– T. b. rhodesiense 386– T. brucei gambiense 385– thiol-dependent peroxidases 201, 202– thiol-dependent redox system 168– thiol redox metabolism 167–173, 387, 388– trypanothione-based redox

metabolism 167–186– – thiol redox metabolism 167–173

Trypanosoma vivax 405trypanosome PEX amino acid sequences 135trypanosome-specific 18S-PCR-RFLP

343, 344trypanosomes, pharmacological

metabolomics 37–49– data analysis 42–44– eflornithine 47, 48– melarsoprol 46, 47– MS-based metabolomics 40–42– new technologies applied to 38–44– nifurtimox in combination therapy

(NECT) 48– NMR-based metabolomics 39, 40– pentamidine 44, 45– sample preparation 38, 39– suramin 45, 46– trypanocidal drugs,metabolic affects 44–48trypanosomiasis 297– cerebral 338– chemotherapy 386– human African trypanosomiasis– – life cycle of T. brucei, causative agent 516– melarsoprol-refractory 413– as neglected tropical diseases (NTDs) 386trypanothione 167, 336, 406– in African trypanosomes 388– – synthesis and reduction 388– Ellman’s-reagent-mediated

regeneration 408trypanothione (bis(glutathionyl)

spermidine 387trypanothione-based redox metabolism– of trypanosomatids 167–186– – thiol redox metabolism 167–173– trypanothione biosynthesis 173–177– trypanothione recycling 177, 178– trypanothione utilization 178–185– – hydroperoxide metabolism 181, 182– – redoxin and DNA synthesis 182, 183, 184– – redoxin-dependent functions 180, 181– – redoxin-independent functions 178– – redoxins and peroxidases as drug

targets 184, 185– – trypanothione-dependent detoxification

reactions and drug resistance 179, 180– – trypanothione-dependent ligation of iron,

NO complexes and ISCs 178, 179trypanothione biosynthesis 173–177– glutathione synthesis 173– polyamine synthesis, salvage, and

uptake 173, 175– trypanothione synthesis 175–177

Index j545

trypanothione-dependent detoxificationreactions 177, 179, 180

trypanothione-dependent glyoxalasepathway 154

trypanothione-dependent hydroperoxidemetabolism 183

trypanothione metabolism 21, 169trypanothione-reactive agents 420– reaction mechanisms– – for modification of protein thiols

(RSH) 421– – for polymer formation and

fragmentation 422– unsaturated mannich bases as dithiol-

alkylating agents 420, 423trypanothione recycling 177, 178trypanothione reductase (TR) 70, 254, 387– active site of T. cruzi TR 390– as drug target molecule 407, 408– inhibitors 63, 140– screening approaches (See screening

approaches towards TR)– turncoat inhibitors (subversive substrates/

redox cyclers) 408, 409– as validated drug target 389– vs. human glutathione reductase (GR)

389, 391trypanothione-related pathways– components 170–172trypanothione-related protein 70trypanothione synthetase (TryS) 175, 226,

387, 429, 430– functional and structural

characteristics 430–436– – alternative routes of T(SH)2

biosynthesis 431– – ATP-grasp fold loop 434– – LmTryS model structure 435– – spermidine and glutathione analogs as

substrates in T(SH)2 biosynthesis 433– – TryS-amidase X-ray structure 432– GSH analogs with inhibitory activity 437– Gsp analogs mimic transition state during

Gsp formation 438– inhibitor design 436–440– natural product with inhibitory activity 440– N5-substituted paullone inhibiting Cf

TryS 438– TryS inhibitors derived from random

screening 439trypanothione system 185, 388trypanothione utilization 178–185– hydroperoxide metabolism 181, 182– redoxin and DNA synthesis 182, 183, 184

– redoxin-dependent functions 180, 181– redoxin-independent functions 178– redoxins and peroxidases as drug

targets 184, 185– trypanothione-dependent– – detoxification reactions and drug

resistance 179, 180– – ligation of iron, NO complexes and

ISCs 178, 179tryparedoxin (Tpx) 204, 388T(SH)2-dependent enzymes 429T(SH)2 synthesis 176tumor necrosis factor (TNF)-a 8, 108, 217TUNEL test 269TXN-dependent peroxidase activity 204type IA DNA topoisomerases 253type II DNA topoisomerase 253

uubiquitin-activating enzyme 184UDP-N-acetylglucosamine pyrophosphorylase

(UAP) 138UDP-glucose-40-epimerase (UGE) 138UDP-glucose pyrophosphorylase (UGP)

138UMS-binding protein (UMSBP) 247, 253– DNA-binding activity and its redox

state 253, 254– surface plasmon resonance (SPR)

analysis 254UMSBP gene 247universal mini circle sequence binding

protein 183uridine-5-monophosphate (UMP)

synthase 132

vvariant surface glycoprotein (VSG) 269,

270, 271– coat 288– VSG-specific antibodies 271, 272vinylsulfone K11777 289virtual screening approaches 65, 72– against trypanosome proteins 67–74virulence 352– factors 228visceral leishmaniasis– anti-leishmanial drugs and treatment

options 4–8– available drugs 4, 5– clinical drug efficacy, regional differences

in 7, 8– clinical features 3– drugs and treatment regimes 6

546j Index

– drugs, pharmacokinetic/pharmacodynamicprofiles 7

– open questions and needs 10– PKDL 8–10– treatments and needs 3–10

wWorld Health Organization 18– guidelines 493– key requirements, for drugs 475– 17 NTDs 386– screening program supported by 417

xxanthine phosphoribosyltransferase

(XPRT) 132xanthine urolithiasis 23X-ray crystallography 67, 68, 69X-ray Trypanosoma’s protein structures– statistics 60

zZ-DNA region 248zinc-dependent protease (MSP-B) 273zoonosis 386, 490

Index j547