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Amantadine Rimantadine

Amantadine has been used for years as a treatment for Parkinson disease. Both of these agents will specifically inhibit replication of the influenza type A viruses at low concentrations. Rimantadine is generally 4 to 10 times more active than amantadine. The adamantanamines have two mechanisms in common: (a) they inhibit an early step in viral replication, most likely viral uncoating,25 and (b) in some strains, they affect a later step that probably involves viral assembly, possibly by interfering with hemagglutinin processing. The main biochemical locus of action is the influenza type A virus M2 protein, which is an integral membrane protein that functions as an ion channel. The M2 channel is a proton transport system. By interfering with the function of the M2 protein, the adamantanamines inhibit acid-mediated dissociation of the ribonucleoprotein complex early in replication. They also interfere with transmembrane proton pumping, maintaining a high intracellular proton concentration relative to the extracellular concentration and enhancing acidic pH-induced conformational changes in the hemagglutinin during its intracellular transport at a later stage. The conformational changes in hemagglutinin prevent transfer of the nascent virus particles to the cell membrane for exocytosis.

Resistant variants of influenza type A have been recovered from amantadine- and rimantadine-treated patients. Resistance with inhibitory concentrations increased more than 100-fold have been associated with single nucleotide changes that lead to amino acid substitutions in the transmembrane domain of M2. Amantadine and rimantadine share cross-susceptibility and resistance.25,26

Amantadine and rimantadine are approved in the United States for prevention and treatment of influenza type A virus infections. Seasonal prophylaxis with either drug is about 70% to 90% protective27 against influenza type A. The drugs have no effect on influenza type B. The primary side effects are related to the central nervous system and are dopaminergic. This is not surprising, because amantadine is used in the treatment of Parkinson disease. Rimantadine has significantly fewer side effects, probably because of its extensive biotransformation. Less than 50% of a dose of rimantadine is excreted unchanged, and more than 20% appears in the urine as metabolites.28 Amantadine is excreted largely unchanged in the urine.

NEURAMINIDASE INHIBITORS: ZANAMIVIR AND OSELTAMIVIR

Sheathing the protein coat of the influenza virus is a lipid envelope. Two macromolecules, surface glycoproteins, are embedded in the lipid envelope: hemagglutinin and neu-raminidase. These glycoproteins fulfill separate functions in the viral cycle. Hemagglutinin is important for binding of the virus to the host cell membrane by a terminal sialic acid residue. Neuraminidase is an enzyme. It functions in several of the early activation steps of the virus and occurs in both influenza A and B viruses. Neuraminidase is believed to be a sialidase, cleaving a bond between a terminal sialic acid unit and a sugar. This action is important in enhancing the penetration of viruses into host cells, and hence enhances the infectivity of the virus. If the sialic acid-sugar bond is prevented from being cleaved, the viruses tend to aggregate and the migration of viruses into host cells is inhibited. Hence, drugs that inhibit neuraminidase should be useful in interfering with infection caused by influenza virus type A and B.

The importance of neuraminidase in the infectivity of influenza types A and B suggests that it should be a good target for the development of antiviral drugs. Indeed, neuraminidase inhibitors are clinically useful agents in blocking the spread of the viruses. The x-ray crystal structure of neuraminidase has been determined, and it shows that the sialic acid-binding site of neuraminidase is nearly identical in influenza types A and B. The transition state of sialic acid cleavage is believed to proceed through a stabilized carbo-nium ion. Drug molecules that have been developed strongly resemble the transition state. The first of these, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid, is a highly active neuraminidase inhibitor but it is not specific for the viral enzyme. This compound has served as a starting point for the development for virus-specific agents. These molecules, zanamivir and oseltamivir, are effective agents in interfering with infection and spread of influenza virus types A and B (recall that amantadine and rimantadine are only effective against type A).

Zanamivir

X-ray crystallography of 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid bound to neuraminidase showed the three-dimensional structure of the receptor site at which the sialic acid units on the virus bind. Zanamivir is identical to 2-deoxy-2,3-dehydro-N-acetylneuraminic acid except that it possesses a guanidino group at position 4 instead of a hy-droxyl group. At positions 119 and 227 of the receptor site, there exist glutamic acid residues. Zanamivir has been shown to form a salt bridge with the guanidine and Glu-119 and a charge transfer interaction with Glu-227. These interactions increase the interaction strength with the enzyme and create an excellent competitive inhibitor and an effective antiviral agent for influenza types A and B.

Human studies have shown that zanamivir is effective when administered before or after exposure to the influenza virus. If administered before exposure to the virus, the drug reduced viral propagation, infectivity, and disease symptoms. If administered after exposure, the drug reduces propagation, viral titer, and illness. Zanamivir is marketed as a dry powder for oral inhalation. It is used in adolescents and adults who have been exposed and are symptomatic for not more than 2 days. Zanamivir is also indicated for prophylactically treating family members of a person who has developed influenza.

Oseltamivir Phosphate

The x-ray crystal structures of neuraminidase and the viral receptor site showed clearly that additional binding sites exist for the C-5 acetamido carbonyl group and the arginine residue at position 152 of the receptor site. In addition, the C-2 carboxyl group of sialic acid binds to Arg 118, Arg 292, and Arg 371. Position C-6 is capable of undergoing a hydrophobic interaction with various amino acids, including Glu, Ala, Arg, and Ile. Maximum binding to neuraminidase occurs when the C-6 substituent is substituted with a nonpolar chain. In oseltamivir, this nonpolar group is 3-pentyl. An important feature of oseltamivir is the ethyl ester, which makes the drug orally efficacious. This drug is the first orally active agent for use against influenza A and B. It is also indicated for the treatment of acute illness. If administered within 2 days after the onset of influenza symptoms, the drug is effective.

Oseltamivir is actually a prodrug in its ethyl ester form. Ester hydrolysis releases the active oseltamivir molecules.

INTERFERONS: INTERFERON ALFA (INTRON A, ROFERON A) AND INTERFERON BETA (BETASERON)

IFNs are extremely potent cytokines that possess antiviral, immunomodulating, and antiproliferative actions.29 IFNs are synthesized by infected cells in response to various inducers (Fig. 9.2) and, in turn, elicit either an antiviral state in neighboring cells or a natural killer cell response that destroys the initially infected cell (Fig. 9.3). There are three classes of human IFNs that possess significant antiviral activity. These are IFN-a (more than 20 subtypes), IFN-jS (2 subtypes), and IFN-y. IFN-a is used clinically in a recombinant form (called interferon alfa). IFN-8 (Betaseron) is a recombinant form marketed for the treatment of multiple sclerosis.

IFN-a and IFN-jS are produced by almost all cells in response to viral challenge. However, interferon production is not limited to viral stimuli. Various other triggers, including cytokines such as interleukin-1, interleukin-2, and tumor necrosis factor, will elicit the production of IFNs. Both IFN-a and IFN-jS are elicited by exposure of a cell to double-stranded viral RNA. IFN-a is produced by lymphocytes and macrophages, whereas IFN-8 is biosynthesized in fibroblasts and epithelial cells. IFN-y production is restricted to T lymphocytes and natural killer cells responding to antigenic stimuli, mitogens, and specific cytokines. IFN-a and IFN-jS bind to the same receptor, and the genes for both are encoded on chromosome 9. The receptor for IFN-y is unique,

Type 1 Interferons IFN-a IFN-/3

Type 2 Interferons IFN-7

Lymphoblasts Macrophages

Fibroblasts, Epithelial Cells

Induced by Double-stranded Viral RNA; Receptors identical

Both encoded on Chromosome 9

Figure 9.2 • Types of interferon.

Mitogen-stimulated T Lymphocytes

Induced by Mitogens or Lectins

Receptor Unlike Type 1

Encoded on Chromosome 12

and only one subtype has been identified. The genes for this molecule are encoded on chromosome 12. IFN-y has less antiviral activity than IFN-a and IFN-jS but more potent immunoregulatory effects. IFN-y is especially effective in activating macrophages, stimulating cell membrane expression of class II major histocompatibility complexes (MHC-II), and mediating the local inflammatory responses. Most animal viruses are sensitive to the antiviral actions of IFNs. The instances in which a virus is insensitive to IFN typically involve DNA viruses.13

On binding to the appropriate cellular receptor, the IFNs induce the synthesis of a cascade of antiviral proteins that contribute to viral resistance. The antiviral effects of the IFNs are mediated through inhibition of30:

• Viral penetration or uncoating

• Synthesis of mRNA

• Translation of viral proteins

• Viral assembly and release

With most viruses, the IFNs predominantly inhibit protein synthesis. This takes place through the intermediacy of IFN-induced proteins such as 2',5'-oligoadenylate (2',5'-OA) synthetases (Fig. 9.4) and a protein kinase, either of which can inhibit viral protein synthesis in the presence of double-stranded RNA. 2',5'-OA activates a cellular endori-bonuclease (RNase) (Fig. 9.5) that cleaves both cellular and viral RNA. The protein kinase selectively phosphorylates and inactivates eukaryotic initiation factor 2 (eIF2), preventing initiation of the mRNA-ribosome complex. IFN also induces a specific phosphodiesterase that cleaves a portion of transfer RNA (tRNA) molecules and thereby interferes with peptide elongation.30 The infection sequence for a given virus may be inhibited at one or several steps. The principal inhibitory effect differs among virus families. Certain viruses can block the production or activity of selected IFN-inducible proteins and thus counter the IFN effect.

IFNs cannot be absorbed orally; to be used therapeutically, they must be given intramuscularly or subcutaneously. The biological effects are quite long, so pharmacokinetic parameters are difficult to determine. The antiviral state in peripheral blood mononuclear cells typically peaks 24 hours after a dose of IFN-a and IFN-jS, then decreases to baseline in 6 days.31 Both recombinant and natural INF-a and INF-jS are approved for use in the United States for the treatment of condyloma acuminatum (venereal warts), chronic hepatitis C, chronic hepatitis B, Kaposi sarcoma in HIV-infected patients, other malignancies, and multiple sclerosis.

Attempts have been made to produce drugs that selectively induce interferon production. One such molecule, tilorone induces interferon in murine models but is not effective in humans.

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