International
Tables for Crystallography Volume F Crystallography of biological macromolecules Edited by M. G. Rossmann and E. Arnold © International Union of Crystallography 2006 |
International Tables for Crystallography (2006). Vol. F. ch. 1.3, pp. 13-15
Section 1.3.4.1. Infectious diseases
aBiomolecular Structure Center, Department of Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7742, USA |
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).
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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.
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).
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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.
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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).
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