Section 1.3.4.1. Infectious diseases

Some icosahedral pathogenic viruses have all their capsid proteins elucidated, while for the more complex viruses like influenza virus, hepatitis C virus (HCV) and HIV, numerous individual protein structures have been solved (Table 1.3.4.1). However, not all 14 native proteins of the HIV genome have yet surrendered to the crystallographic community, nor to the NMR spectroscopists or the high-resolution electron microscopists, our partners in experimental structural biology (Turner & Summers, 1999). Nevertheless, the structures of HIV protease, reverse transcriptase and fragments of HIV integrase and of HIV viral core and surface proteins are of tremendous value for developing novel anti-AIDS therapeutics [Arnold et al., 1996; Lin et al., 1998; Wlodawer & Vondrasek, 1998; see also references in Table 1.3.4.1(a)]. A similar situation occurs for hepatitis C virus. The protease structure of this virus has been solved recently (simultaneously by four groups!), as well as its helicase structure, providing platforms on the basis of which the design of novel drugs is actively pursued (Le et al., 1998).

Table 1.3.4.1| top | pdf | Important human pathogenic viruses and their proteins (a) RNA viruses (i) Single-stranded Family Example Protein structures solved Reference Arenaviridae Lassa fever virus None   Bunyaviridae Hantavirus None   Caliciviridae Hepatitis E virus, Norwalk virus None   Coronaviridae Corona virus None   Deltaviridae Hepatitis D virus Oligomerization domain of antigen [1] Filoviridae Ebola virus GP2 of membrane fusion glycoprotein [2] Flaviviridae Dengue NS3 protease [3] Hepatitis C NS3 protease [4], [5] RNA helicase [6] Yellow fever None   Tick-borne encephalitis virus Envelope glycoprotein [7] Orthomyxoviridae Influenza virus Neuraminidase [8] Haemagglutinin [9] Matrix protein M1 [10] Paramyxoviridae Measles, mumps, parainfluenza, respiratory syncytial virus None   Picornaviridae Hepatitis A virus 3C protease [11] Poliovirus Capsid [12] RNA-dependent polymerase [13] Rhinovirus Capsid [14] 3C protease [15] Echovirus Capsid [16] Retroviridae HIV Capsid protein [17] Matrix protein [18] Protease [19], [20], [21] Reverse transcriptase [22], [23], [47], [48], [49] Integrase [24] gp120 [25] NEF [26] gp41 [27] Rhabdovirus Rabies virus None   Togaviridae Rubella None   (ii) Double-stranded Family Example Protein structures solved Reference Reoviridae Rotavirus None   (b) DNA viruses (i) Single-stranded Family Example Protein structures solved Reference Parvoviridae B 19 virus None   (ii) Double-stranded Family Example Protein structures solved Reference Adenoviridae Adenovirus Protease [28] Capsid [29] Knob domain of fibre protein [30] Hepadnaviridae Hepatitis B Capsid [31] Herpesviridae Cytomegalovirus Protease [32], [33], [34] Epstein–Barr virus Domains of nuclear antigen 1 [35] BCRF1 [36] Herpes simplex Protease [37] Thymidine kinase [38] Uracyl-DNA glycosylase [39] Core of VP16 [40] Varicella zoster Protease [42] Papovaviridae Papillomavirus DNA-binding domain of E2 [43] Activation domain of E2 [44] Poxviridae Smallpox virus None   Vaccinia virus (related to smallpox but non-pathogenic) Methyltransferase VP39 [45] Domain of topoisomerase [46] References: [1] Zuccola et al. (1998); [2] Weissenhorn et al. (1998); [3] Murthy et al. (1999); [4] Love et al. (1996); [5] Yan et al. (1998); [6] Yao et al. (1997); [7] Rey et al. (1995); [8] Varghese et al. (1983); [9] Wilson et al. (1981); [10] Sha & Luo (1997); [11] Allaire et al. (1994); [12] Hogle et al. (1985); [13] Hansen et al. (1997); [14] Rossmann et al. (1985); [15] Matthews et al. (1994); [16] Filman et al. (1998); [17] Worthylake et al. (1999); [18] Hill et al. (1996); [19] Navia, Fitzgerald et al. (1989); [20] Wlodawer et al. (1989); [21] Erickson et al. (1990); [22] Rodgers et al. (1995); [23] Ding et al. (1995); [24] Dyda et al. (1994); [25] Kwong et al. (1998); [26] Lee et al. (1996); [27] Chan et al. (1997); [28] Ding et al. (1996); [29] Roberts et al. (1986); [30] Xia et al. (1994); [31] Wynne et al. (1999); [32] Tong et al. (1996); [33] Qiu et al. (1996); [34] Shieh et al. (1996); [35] Bochkarev et al. (1995); [36] Zdanov et al. (1997); [37] Hoog et al. (1997); [38] Wild et al. (1995); [39] Savva et al. (1995); [40] Liu et al. (1999); [42] Qiu et al. (1997); [43] Hegde & Androphy (1998); [44] Harris & Botchan (1999); [45] Hodel et al. (1996); [46] Sharma et al. (1994); [47] Kohlstaedt et al. (1992); [48] Jacobo-Molina et al. (1993); [49] Ren et al. (1995).

A quite spectacular example of how structural knowledge can lead to the synthesis of powerful inhibitors is provided by influenza virus neuraminidase. The structure of a neuraminidase–transition-state analogue complex suggested the addition of positively charged amino and guanidinium groups to the C4 position of the analogue, which resulted, in one step, in a gain of four orders of magnitude in binding affinity for the target enzyme (von Itzstein et al., 1993).

A very large number of structures of important drug target proteins of bacterial origin have been solved crystallographically (Table 1.3.4.2). Currently, the most important single infectious bacterial agent is Mycobacterium tuberculosis, with three million deaths and eight million new cases annually (Murray & Salomon, 1998). The crystal structures of several M. tuberculosis potential and proven drug target proteins have been elucidated (Table 1.3.4.2). The complete M. tuberculosis genome has been sequenced recently (Cole et al., 1998), and this will undoubtedly have a tremendous impact on future drug development.

Table 1.3.4.2| top | pdf | Protein structures of important human pathogenic bacteria Organism Disease(s) Protein structures solved Reference Staphylococcus aureus Abscesses Alpha-haemolysin [1] Endocarditis Aureolysin [2] Gastroenteritis Beta-lactamase [3] Toxic shock syndrome Collagen adhesin [4] 7,8-Dihydroneopterin aldolase [5] Dihydropteroate synthetase [6] Enterotoxin A [7] Enterotoxin B [8] Enterotoxin C2 [9] Enterotoxin C3 [10] Exfoliative toxin A [11] Ile-tRNA-synthetase [12] Kanamycin nucleotidyltransferase [13] Leukocidin F [14] Nuclease [15] Staphopain [16] Staphylokinase [17] Toxic shock syndrome toxin-1 [18] Staphylococcus epidermidis Implant infections None   Enterococcus faecalis Urinary tract and biliary tract infections NADH peroxidase [19] (Streptococcus faecalis)   Histidine-containing phosphocarrier protein [20] Streptococcus mutans Endocarditis Glyceraldehyde-3-phosphate dehydrogenase [21] Streptococcus pneumoniae Pneumonia Penicillin-binding protein PBP2x [22] Meningitis, upper respiratory tract infections Dpnm DNA adenine methyltransferase [23] Streptococcus pyogenes Pharyngitis Inosine monophosphate dehydrogenase [24] Scarlet fever, toxic shock syndrome, immunologic disorders (acute glomerulonephritis and rheumatic fever) Pyrogenic exotoxin C [25] Bacillus anthracis Anthrax Anthrax protective antigen [26] Bacillus cereus Food poisoning Beta-amylase [27] Beta-lactamase II [28] Neutral protease [29] Oligo-1,6-glucosidase [30] Phospholipase C [31] Clostridium botulinum Botulism Neurotoxin type A [32] Clostridium difficile Pseudomembranous colitis None   Clostridium perfringens Gas gangrene Alpha toxin [33] Food poisoning Perfringolysin O [34] Clostridium tetani Tetanus Toxin C fragment [35] Corynebacterium diphtheriae Diphtheria Toxin [36] Toxin repressor [37] Listeria monocytogenes Meningitis, sepsis Phosphatidylinositol-specific phospholipase C [38] Actinomyces israelii Actinomycosis None   Nocardia asteroides Nocardiosis None   Neisseria gonorrhoeae Gonorrhea Type 4 pilin [39] Carbonic anhydrase [40] Neisseria meningitidis Meningitis Dihydrolipoamide dehydrogenase [41] Bordetella pertussis Whooping cough Toxin [42] Virulence factor P.69 [43] Brucella sp. Brucellosis None   Campylobacter jejuni Enterocolitis None   Enterobacter cloacae Urinary tract infection, pneumonia Beta-lactamase: class C [44] UDP-N-acetylglucosamine enolpyruvyltransferase [45] Escherichia coli        ETEC (enterotoxigenic) Traveller's diarrhoea Heat-labile enterotoxin [46] Heat-stable enterotoxin (is a peptide) [47]  EHEC (enterohaemorrhagic) HUS Verotoxin-1 [48]  EPEC (enteropathogenic) Diarrhoea None    EAEC (enteroaggregative) Diarrhoea None    EIEC (enteroinvasive) Diarrhoea None    UPEC (uropathogenic)   FimH adhesin [49] FimC chaperone [49] PapD [50]  NMEC (neonatal meningitis) Meningitis None   Franciscella tularensis Tularemia None   Haemophilus influenzae Meningitis, otitis media, pneumonia Diaminopimelate epimerase [51] 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase [52] Ferric iron binding protein Mirp [53] Klebsiella pneumoniae Urinary tract infection, pneumonia, sepsis β-Lactamase SHV-1 [54] Legionella pneumophila Pneumonia None   Pasteurella multocida Wound infection None   Proteus mirabilis Pneumonia, urinary tract infection Catalase [55] Glutathione S-transferase [56] Proteus vulgaris Urinary tract infections Pvu II DNA-(cytosine N4) methyltransferase [57] Pvu II endonuclease [58] Tryptophanase [59] Salmonella typhi Typhoid fever None, but many for S. typhimurium linked with zoonotic disease   Salmonella enteridis Enterocolitis None   Serratia marcescens Pneumonia, urinary tract infection Serralysin [60] Aminoglycoside 3-N-acetyltransferase [61] Chitinase A [62] Chitobiase [63] Endonuclease [64] Hasa (haemophore) [65] Prolyl aminopeptidase [66] Shigella sp. Dysentery Chloramphenicol acetyltransferase [67] Shiga-like toxin I [68] Vibrio cholerae Cholera Cholera toxin [69], [70] DSBA oxidoreductase [71] Neuraminidase [104] Yersinia enterocolitica Enterocolitis Protein-Tyr phosphatase YOPH [72] Yersinia pestis Plague None   Pseudomonas aeruginosa Wound infection, urinary tract infection, pneumonia, sepsis Alkaline metalloprotease [73] Amidase operon [74] Azurin [75] Cytochrome 551 [76] Cytochrome c peroxidase [77] Exotoxin A [78] p-Hydroxybenzoate hydroxylase [79] Hexapeptide xenobiotic acetyltransferase [80] Mandelate racemase [81] Nitrite reductase [82] Ornithine transcarbamoylase [83] Porphobilinogen synthase [84] Pseudolysin [85] Burkholderia cepacia Wound infection, urinary tract infection, pneumonia, sepsis Biphenyl-cleaving extradiol dioxygenase [86] cis-Biphenyl-2,3-dihydrodiol-2,3-dehydrogenase [87] Dialkylglycine decarboxylase [88] Lipase [89] Phthalate dioxygenase reductase [90] Stenotrophomonas maltophilia (= Pseudomonas maltophilia) Sepsis None   Bacteroides fragilis Intra-abdominal infections Beta-lactamase type 2 [91] Mycobacterium leprae Leprosy Chaperonin-10 (GroES homologue) [92] RUVA protein [93] Mycobacterium tuberculosis Tuberculosis 3-Dehydroquinate dehydratase [94] Dihydrofolate reductase [95] Dihydropteroate synthase [96] Enoyl acyl-carrier-protein reductase (InhA) [97] Mechanosensitive ion channel [98] Quinolinate phosphoribosyltransferase [99] Superoxide dismutase (iron dependent) [100] Iron-dependent repressor   Mycobacterium bovis Tuberculosis Tetrahydrodipicolinate-N-succinyltransferase [102] Chlamydia psitacci Psittacosis None   Chlamydia pneumoniae Atypical pneumonia None   Chlamydia trahomatis Ocular, respiratory and genital infections None   Coxiella burnetii Q fever None   Rickettsia sp. Rocky Mountain spotted fever None   Borrelia burgdorferi Lyme disease Outer surface protein A [103] Leptospira interrogans Leptospirosis None   Treponema pallidum Syphilis None   Mycoplasma pneumoniae Atypical pneumonia None   References: [1] Song et al. (1996); [2] Banbula et al. (1998); [3] Herzberg & Moult (1987); [4] Symersky et al. (1997); [5] Hennig et al. (1998); [6] Hampele et al. (1997); [7] Sundstrom et al. (1996); [8] Papageorgiou et al. (1998); [9] Papageorgiou et al. (1995); [10] Fields et al. (1996); [11] Vath et al. (1997); [12] Silvian et al. (1999); [13] Pedersen et al. (1995); [14] Pedelacq et al. (1999); [15] Loll & Lattman (1989); [16] Hofmann et al. (1993); [17] Rabijns et al. (1997); [18] Prasad et al. (1993); [19] Yeh et al. (1996); [20] Jia et al. (1993); [21] Cobessi et al. (1999); [22] Pares et al. (1996); [23] Tran et al. (1998); [24] Zhang, Evans et al. (1999); [25] Roussel et al. (1997); [26] Petosa et al. (1997); [27] Mikami et al. (1999); [28] Carfi et al. (1995); [29] Pauptit et al. (1988); [30] Watanabe et al. (1997); [31] Hough et al. (1989); [32] Lacy et al. (1998); [33] Naylor et al. (1998); [34] Rossjohn, Feil, McKinstry et al. (1997); [35] Umland et al. (1997); [36] Choe et al. (1992); [37] Qiu et al. (1995); [38] Moser et al. (1997); [39] Parge et al. (1995); [40] Huang, Xue et al. (1998); [41] Li de la Sierra et al. (1997); [42] Stein et al. (1994); [43] Emsley et al. (1996); [44] Lobkovsky et al. (1993); [45] Schonbrunn et al. (1996); [46] Sixma et al. (1991); [47] Ozaki et al. (1991); [48] Stein et al. (1992); [49] Choudhury et al. (1999); [50] Sauer et al. (1999); [51] Cirilli et al. (1993); [52] Hennig et al. (1999); [53] Bruns et al. (1997); [54] Kuzin et al. (1999); [55] Gouet et al. (1995); [56] Rossjohn, Polekhina et al. (1998); [57] Gong et al. (1997); [58] Athanasiadis et al. (1994); [59] Isupov et al. (1998); [60] Baumann (1994); [61] Wolf et al. (1998); [62] Perrakis et al. (1994); [63] Tews et al. (1996); [64] Miller et al. (1994); [65] Arnoux et al. (1999); [66] Yoshimoto et al. (1999); [67] Murray et al. (1995); [68] Ling et al. (1998); [69] Merritt et al. (1994); [70] Zhang et al. (1995); [71] Hu et al. (1997); [72] Stuckey et al. (1994); [73] Miyatake et al. (1995); [74] Pearl et al. (1994); [75] Adman et al. (1978); [76] Almassy & Dickerson (1978); [77] Fulop et al. (1995); [78] Allured et al. (1986); [79] Gatti et al. (1994); [80] Beaman et al. (1998); [81] Kallarakal et al. (1995); [82] Nurizzo et al. (1997); [83] Villeret et al. (1995); [84] Frankenberg et al. (1999); [85] Thayer et al. (1991); [86] Han et al. (1995); [87] Hulsmeyer et al. (1998); [88] Toney et al. (1993); [89] Kim et al. (1997); [90] Correll et al. (1992); [91] Concha et al. (1996); [92] Mande et al. (1996); [93] Roe et al. (1998); [94] Gourley et al. (1999); [95] Li et al. (2000); [96] Baca et al. (2000); [97] Dessen et al. (1995); [98] Chang, Spencer et al. (1998); [99] Sharma et al. (1998); [100] Cooper et al. (1995); [102] Beaman et al. (1997); [103] Li et al. (1997); [104] Crennell et al. (1994).

The crystal structures of many bacterial dihydrofolate reductases, the target of several antimicrobials including trimethoprim, have also been reported. Recently, the atomic structure of dihydropteroate synthase (DHPS), the target of sulfa drugs, has been elucidated, almost 60 years after the first sulfa drugs were used to treat patients (Achari et al., 1997; Hampele et al., 1997).

A very special set of bacterial proteins are the toxins. Some of these have dramatic effects, with even a single molecule able to kill a host cell. These toxins outsmart and (mis)use many of the defence systems of the host, and their structures are often most unusual and fascinating, as recently reviewed by Lacy & Stevens (1998). The structures of the toxins are actively used for the design of prophylactics and therapeutic agents to treat bacterial diseases [see e.g. Merritt et al. (1997), Kitov et al. (2000) and Fan et al. (2000)]. It is remarkable that the properties of these devastating toxins are also used, or at least considered, for the treatment of disease, such as in the engineering of diphtheria toxin to create immunotoxins for the treatment of cancer and the deployment of cholera toxin mutants as adjuvants in mucosal vaccines. Knowledge of the three-dimensional structures of these toxins assists in the design of new therapeutically useful proteins.

A major cause of death and worldwide suffering is due to infections by several protozoa, including:

Drug resistance, combined with other factors, has been the cause of a major disappointment for the early hopes of a `malaria eradication campaign'. Fortunately, new initiatives have been launched recently under the umbrella of the `Malaria roll back' program and the `Multilateral Initiative for Malaria' (MIM). We are facing a formidable challenge, however, since the parasite is very clever at evading the immune response of the human host. Drugs are the mainstay of current treatments and may well be so for a long time to come. Protein crystallographic studies of Plasmodium proteins are hampered by the unusual codon usage of the Plasmodium species, coupled with a tendency to contain insertions of numerous hydrophilic residues in the polypeptide chain (Gardner et al., 1998) which provide sometimes serious obstacles to obtaining large amounts of Plasmodium proteins for structural investigations.

However, the structures of an increasing number of potential drug targets from these protozoan parasites are being unravelled. These include the variable surface glycoproteins (VSGs) and glycolytic enzymes of Trypanosoma brucei, crucial malaria proteases, and the remarkable trypanothione reductase (Table 1.3.4.3). The structures of nucleotide phosphoribosyl transferases of a variety of protozoan parasites have also been elucidated. Moreover, the structure of DHFR from Pneumocystis carinii, the major opportunistic pathogen in AIDS patients in the United States, has been determined. Several of these structures are serving as starting points for the development of new drugs.

Table 1.3.4.3| top | pdf | Protein structures of important human pathogenic protozoa, fungi and helminths (a) Protozoa Organism Disease Protein structures solved Reference Acanthamoeba sp. Opportunistic meningoencephalitis, corneal ulcers Actophorin [1] Profilin [2] Cryptosporidium parvum Cryptosporidiosis None   Entamoeba histolytica Amoebic dysentery, liver abscesses None   Giardia lamblia Giardiasis None   Leishmania sp. Leishmaniasis Adenine phosphoribosyltransferase [3] Dihydrofolate reductase-thymidylate synthase [4] Glyceraldehyde-3-phosphate dehydrogenase [5] Leishmanolysin [6] Nucleoside hydrolase [7] Pyruvate kinase [8] Triosephosphate isomerase [9] Plasmodium sp. Malaria Fructose-1,6-bisphosphate aldolase [10] Lactate dehydrogenase [11] MSP1 [12] Plasmepsin II [13] Purine phosphoribosyltransferase [14] Triosephosphate isomerase [15] Pneumocystis carinii Pneumonia Dihydrofolate reductase [16] Toxoplasma gondii Toxoplasmosis HGXPRTase [17] UPRTase [18] Trichomonas vaginalis Trichomoniasis None   Trypanosoma brucei Sleeping sickness Fructose-1,6-bisphosphate aldolase [19] Glyceraldehyde-3-phosphate dehydrogenase [20] 6-Phosphogluconate dehydrogenase [21] Phosphoglycerate kinase [22] Triosephosphate isomerase [23] VSG [24] Trypanosoma cruzi Chagas' disease Cruzain (cruzipain) [25] Glyceraldehyde-3-phosphate dehydrogenase [26] Hypoxanthine phosphoribosyltransferase [27] Triosephosphate isomerase [28] Trypanothione reductase [29] Tyrosine aminotransferase [30] (b) Fungi Organism Disease Protein structures solved Reference Aspergillus fumigatus Aspergillosis Restrictocin [31] Blastomyces dermatidis Blastomycosis None   Candida albicans Candidiasis Dihydrofolate reductase [32] N-Myristoyl transferase [33] Phosphomannose isomerase [34] Secreted Asp protease [35] Coccidiodes immitis Coccidioidomycosis None   Cryptococcus neoformans Cryptococcosis None   Histoplasma capsulatum Histoplasmosis None   Mucor sp. Mucormycosis None   Paracoccidioides brasiliensis Paracoccidioidomycosis None   Rhizopus sp. Phycomycosis Lipase II [36] Rhizopuspepsin [37] RNase Rh [38] (c) Helminths Organism Disease Protein structures solved Reference Clonorchis sinensis Clonorchiasis None   Fasciola hepatica Fasciolasis Glutathione S-transferase [39] Fasciolopsis buski Fasciolopsiasis None   Paragominus westermani Paragonimiasis None   Schistosoma sp. Schistosomiasis Glutathione S-transferase [39], [40] Hexokinase [41] Diphyllobotrium latum Diphyllobothriasis None   Echinococcus granulosus Unilocular hydatid cyst disease None   Taenia saginata Taeniasis None   Taenia solium Taeniasis None   Ancylostoma duodenale Old World hookworm disease None   Anisakis Anisakiasis None   Ascaris lumbricoides Ascariasis Haemoglobin [42] Major sperm protein [43] Trypsin inhibitor [44] Enterobius vermicularis Pinworm infection None   Necator New World hookworm disease None   Strongyloides stercoralis Strongyloidiasis None   Trichinella spiralis Trichinosis None   Trichuris trichiura Whipworm infection None   Brugia malayi Filariasis Peptidylprolyl isomerase [45], [46] Dracunculus medinensis Guinea worm disease None   Loa loa Loiasis None   Onchocerca volvulus River blindness None   Toxocara canis Visceral larva migrans None   Wuchereria bancrofti Lymphatic filariasis (elephantiasis) None   References: [1] Leonard et al. (1997); [2] Liu et al. (1998); [3] Phillips et al. (1999); [4] Knighton et al. (1994); [5] Kim et al. (1995); [6] Schlagenhauf et al. (1998); [7] Shi, Schramm & Almo (1999); [8] Rigden et al. (1999); [9] Williams et al. (1999); [10] Kim et al. (1998); [11] Read et al. (1999); [12] Chitarra et al. (1999); [13] Silva et al. (1996); [14] Shi, Li et al. (1999); [15] Velanker et al. (1997); [16] Champness et al. (1994); [17] Schumacher et al. (1996); [18] Schumacher et al. (1998); [19] Chudzik et al. (2000); [20] Vellieux et al. (1993); [21] Phillips et al. (1998); [22] Bernstein et al. (1998); [23] Wierenga et al. (1987); [24] Freymann et al. (1990); [25] McGrath et al. (1995); [26] Souza et al. (1998); [27] Focia et al. (1998); [28] Maldonado et al. (1998); [29] Lantwin et al. (1994); [30] Blankenfeldt et al. (1999); [31] Yang & Moffat (1995); [32] Whitlow et al. (1997); [33] Weston et al. (1998); [34] Cleasby et al. (1996); [35] Cutfield et al. (1995); [36] Kohno et al. (1996); [37] Suguna et al. (1987); [38] Kurihara et al. (1992); [39] Rossjohn, Feil, Wilce et al. (1997); [40] McTigue et al. (1995); [41] Mulichak et al. (1998); [42] Yang et al. (1995); [43] Bullock et al. (1996); [44] Huang et al. (1994); [45] Mikol et al. (1998); [46] Taylor et al. (1998).

In general, the human immune system is able to keep the growth of fungi under control, but in immuno-compromised patients (e.g. as a result of cancer chemotherapy, HIV infection, transplantation patients receiving immunosuppressive drugs, genetic disorders) such organisms are given opportunities they usually do not have. Candida albicans is an opportunistic fungal organism which causes serious complications in immuno-compromised patients. Several of its proteins have been structurally characterized (Table 1.3.4.3) and provide opportunities for the development of selectively active inhibitors.

Worms affect the lives of billions of human beings, causing serious morbidity in many ways. Onchocerca volvolus is the cause of river blindness, which resulted in the virtual disappearance of entire villages in West Africa, until ivermectin appeared. This remarkable compound dramatically reduced the incidence of the disease, even though it does not kill the adult worms. Therefore, a biological clock is ticking, waiting until resistance occurs against this single compound available for treatment. Schistosoma species are responsible for a wide variety of liver diseases and are spreading continuously since irrigation schemes provide a perfect environment for the intermediate snail vector. Other medically important helminths are Wuchereria bancrofti and Brugia malayi. Only a few protein structures from these very important disease-causing organisms have been unravelled so far (Table 1.3.4.3).