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Document Figure 2 A simplified schematic of the replication cycle of an influenza virion in the host respiratory epithelia. Details of viral transport through mucin and pathways of viral spread on budding from the epithelial cell membrane during replication is not understood. Neuraminidase activity is important for release of budding progeny virions, desialyation of viral glycoproteins, and probably facilitates transport through sialic-acidrich mucin. Page 461 Release of virions occur 8 hours post infection and the onset of infection is sudden, resulting in pyroxia, muscular and joint pain, and a dry cough [6]. Virus shedding continues for up to a week, when a rise in virus-specific antibody clears the virus from the host. The vulnerability of the host succumbing to viremea during this week of rising viral titer is mediated by interferon induction [7] 48 hours post infection, which attenuates viral replication until the cell-mediated immune response begins to clear the virus. The severity of the illness is thought to depend on the level of cross protection arising from antibodies raised from previous influenza infections [19]. The course of the illness can be debilitating, and no effective treatment is available at present to halt the progression of the disease. Death can result for susceptible populations (neonate and elderly) primarily as a result of secondary infections [8]. This chapter shall examine a structural basis for the continual emergence of new influenza strains, and the reasons current vaccines against influenza fail to protect against all http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_461.html (1 of 2) [4/9/2004 12:13:07 AM]
Document Page 462 strains of influenza. The discovery of the active site of influenza neuraminidase and the exploitation of its structural conservation shall be discussed in terms of the design of potent neuraminidase inhibitors. The potential therapeutic use of these inhibitors as antiviral drugs against influenza virus infections shall be examined. A. Antigenic Variation The plethora of different strains of virus that are responsible for the continued reinfection of virus in humans is primarily related to mutations in the viral genes of two surface glycoproteins, hemagglutinin and neuraminidase [9]. The current paradigm for this genetic variation [10,11] is that these mutations arise primarily from incremental changes in the amino acid sequences of these glycoproteins by selection pressure of the immune system of the infected host. This mechanism termed “Antigenic Drift” accounts for most of the strain variation within a particular subtype of influenza. However, infrequently a mutation arises by genetic reassortment of viruses from different animal hosts (“Antigenic Shift”) whereby an entirely new gene for one of the surface glycoproteins is generated that is significantly different (~50%) in amino acid sequence from the parent virus. This is the mechanism by which new subtypes of influenza arise and are primarily responsible for the major pandemics that occur. Strains of influenza virus are classified by type (A, B, or C), geographic location, date of original isolation, and the subtype of the hemagglutinin and neuraminidase antigens. There exist 9 known subtypes (N1 to N9) of neuraminidase and 13 known subtypes (H1 to H13) of hemagglutinin for influenza A in all animal populations. Two neuraminidase (N1 and N2) and three hemagglutinin (H1, H2, and H3) subtypes of influenza A have occurred in strains that have infected humans since 1933 when isolates were first characterized [12]. Prior to 1933 there is indirect evidence of antigenic shift occurring in human populations [13]. The N1 subtype was associated with virus isolated between 1933 and 1957, after which time the N2 subtype appeared in the Asian influenza. No major change in the structure of neuraminidase has occurred since, although the hemagglutinin subtype has changed from H2 to H3 in 1968 in the Hong Kong pandemic, and H1N1 reappeared in 1978 as the Russian pandemic. Influenza B, which infects only human hosts, has only one subtype, but like type A undergoes continual antigenic drift. B. Current Therapeutics Amantidine and Rimantidine are the only class of drugs that have been approved for therapy. At high concentration (>50 mg/mL) Amantidine is thought to buffer the pH of the endosome and prevent the conformational http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_462.html [4/9/2004 12:13:12 AM]
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Structure-based Drug Design 14 Stru
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Document Table 3 HIV-1 RT Amino Aci
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Document dine) and didanosine (dide
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Document Page 108 mulate during tre
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Page 535 and 536: Document receptor antagonist into a
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Page 541 and 542: Document 17 Structure and Functiona
Page 543 and 544: Document Table 1 Approval Indicatio
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Page 553 and 554: Document Figure 4 Stereo view of IF
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Page 557 and 558: Document Figure 6 Proposed receptor
Page 559 and 560: Document Page 451 with the cytoplas
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Page 583 and 584: Document Page 471 molecules in the
Page 585 and 586: Document hydroxy, and 6 Neu5Ac2en -
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Page 589 and 590: Document Page 476 nM, respectively.
Page 591 and 592: Document Page 478 lished—was asso
Page 593 and 594: Document VI. Conclusion Page 480 It
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Page 611 and 612: Document A. The Canyon Page 491 The
Page 613 and 614: Document Subsequent studies have sh
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Page 617 and 618: Document Figure 4 A ribbon diagram
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Document D ddI, 152 tumour necrosis
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