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Antivirals: Treatment, Prophylaxis and Pandemic Control

Mechanisms of action of antivirals

Amantadine and rimantadine were the first generation of influenza antiviral agents. 1 x FG Hayden, FY Aoki. Amantadine, rimantadine, and related agents. SL Barriere (Ed.) Antimicrobial Therapy and Vaccines (Williams & Wilkins, Baltimore, 1999) (1344 - 1365) These compounds specifically block the ion channel function of the M2 protein of influenza A virus (see Chapter 2), thus interfering with corresponding specific steps in the viral life cycle. The neuraminidase inhibitors are novel drugs, designed on the basis of the three-dimensional structure of the influenza A and B neuraminidase 2 x PM Colman. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci 3 (1994) (1687 - 1696) Crossref. (see Chapter 2). The mechanisms of action of the four available specific anti-influenza viral drugs are summarized in Figure 22 .

Figure 22 The mechanism by which antiviral drugs interrupt the replicative cycle of influenza is illustrated. M2 inhibitors prevent the M2-mediated acidification of the interior of the virus while it resides in endosomes and the subsequent uncoating of the viral genome, thus inhibiting viral replication. Neuraminidase inhibitors (NAIs) prevent cleavage of sialic acid residues and thus newly formed virus cannot be released from the cell surface to infect adjacent cells; also, virus particles remain associated to one another. source: “The treatment of influenza with antiviral drugs” – Reprinted from CMAJ 07-Jan-03; 168(1): 49–57 by permission of the publisher. © 2003 CMA Media Inc.

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References in context

  • The mechanisms of action of the four available specific anti-influenza viral drugs are summarized in Figure 22.
    Go to context

  • In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface.4 Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein (Figure 22).
    Go to context

  • In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface.4 Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein (Figure 22).
    Go to context

Key Messages

  • Antibiotics are often inappropriately prescribed when uncomplicated influenza infection presents to the physician.
  • Antiviral drugs must be initiated within 24–48 hours of the onset of symptoms for the treatment of influenza.
  • Antiviral drugs must be taken daily through the period of exposure risk for effective prophylaxis against influenza.
  • The use of M2 inhibitors has been limited by the induction of drug-resistant strains of influenza.
  • Particularly in older people, the use of M2 inhibitors has been limited by their adverse effects and need for dose adjustment due to renal excretion of the drugs.
  • In the case of neuraminidase inhibitors, there are thus far few observations of induction of drug-resistant virus strains, although the emergence of Tamiflu-resistant H5N1 virus has been reported.
  • In contrast to the M2 inhibitors, neuraminidase inhibitors have fewer adverse side effects.
  • In the initial phase of an influenza pandemic, antivirals will be the only means to combat its impact.
  • Multiple drug strategies for prophylaxis and treatment may be needed to address the issues of antiviral resistance in an influenza pandemic.
The M2 channel inhibitors – amantadine and rimantadine

At high concentrations (>15 µg/ml), amantadine and rimantadine non-specifically raise the pH within cellular endosomes, thus inhibiting or retarding the acid-induced conformational change in the viral HA. However, the required concentrations of the drugs are not generally attained in vivo. At low, pharmacologically relevant concentrations (<0.75 µg/ml), amantadine and rimantadine specifically inhibit the ion channel activity of the M2 protein, probably through direct binding to the pore region of the protein. 3 x C Wang, K Takeuchi, LH Pinto, RA Lamb. Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J Virol 67 (1993) (5585 - 5594) In doing so, the drugs inhibit acidification of the interior of susceptible viruses and dissociation of the M1 protein from the viral nucleocapsid ( Figure 22 ), which is a necessary step in the uncoating of the viral genome during infection (see Chapter 2). In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface. 4 x RW Ruigrok, EM Hirst, AJ Hay. The specific inhibition of influenza A virus maturation by amantadine: an electron microscopic examination. J Gen Virol 72 (1991) (191 - 194) Crossref. Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein ( Figure 22 ).

The neuraminidase inhibitors – zanamivir and oseltamivir

Influenza A and B viruses (but not influenza C viruses) possess neuraminidase on their outer surface, an enzyme essential for release of virus particles from infected cells, for prevention of formation of viral aggregates and for viral spread within the respiratory tract. 2 x PM Colman. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci 3 (1994) (1687 - 1696) Crossref. Neuraminidase cleaves the receptor for influenza A and B viruses, sialic acid, from glycoproteins and glycolipids. Zanamivir and oseltamivir are analogues of sialic acid, as shown in Figure 23 . 2 x PM Colman. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci 3 (1994) (1687 - 1696) Crossref. These compounds specifically inhibit all nine NA subtypes in nature, including the subtypes contained in the avian strains of influenza A H5N1, H7N7 and H9N2 that have infected humans (see also Chapter 3).

Figure 23 The neuraminidase inhibitors zanamivir and oseltamivir are structural analogs of sialic acid, which is the substrate of neuraminidase (NA) and the receptor for the influenza virus HA. Zanamivir and oseltamivir bind to the substrate binding site of NA, thus blocking its enzymatic activity. Zanamivir (GG167 or Relenza®) is inhaled or administered intranasally. Oseltamivir is given as the oral prodrug oseltamivir phosphate (GS4104 or Tamiflu®), which is converted in the liver to oseltamivir carboxylate GS4071, the active drug.

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References in context

  • Zanamivir and oseltamivir are analogues of sialic acid, as shown in Figure 23.2 These compounds specifically inhibit all nine NA subtypes in nature, including the subtypes contained in the avian strains of influenza A H5N1, H7N7 and H9N2 that have infected humans (see also Chapter 3).
    Go to context

The inhibition of neuraminidase on both influenza A and B viruses has three important consequences. 2 x PM Colman. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci 3 (1994) (1687 - 1696) Crossref. First, it hinders the passage of the virus through the mucus of the respiratory tract and thus retards initial infection of epithelial cells. Second, it inhibits the release of new viral particles from the surface of infected cells and thus slows the spreading of the virus through the respiratory tract of the host. Third, as inhibition of neuraminidase interrupts the release of virus particles from infected cells, it also inhibits transmission of the virus from one infected individual to another.

 
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Figure 22 The mechanism by which antiviral drugs interrupt the replicative cycle of influenza is illustrated. M2 inhibitors prevent the M2-mediated acidification of the interior of the virus while it resides in endosomes and the subsequent uncoating of the viral genome, thus inhibiting viral replication. Neuraminidase inhibitors (NAIs) prevent cleavage of sialic acid residues and thus newly formed virus cannot be released from the cell surface to infect adjacent cells; also, virus particles remain associated to one another. source: “The treatment of influenza with antiviral drugs” – Reprinted from CMAJ 07-Jan-03; 168(1): 49–57 by permission of the publisher. © 2003 CMA Media Inc.

f07-22-9780723434337

References in context

  • The mechanisms of action of the four available specific anti-influenza viral drugs are summarized in Figure 22.
    Go to context

  • In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface.4 Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein (Figure 22).
    Go to context

  • In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface.4 Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein (Figure 22).
    Go to context

Figure 23 The neuraminidase inhibitors zanamivir and oseltamivir are structural analogs of sialic acid, which is the substrate of neuraminidase (NA) and the receptor for the influenza virus HA. Zanamivir and oseltamivir bind to the substrate binding site of NA, thus blocking its enzymatic activity. Zanamivir (GG167 or Relenza®) is inhaled or administered intranasally. Oseltamivir is given as the oral prodrug oseltamivir phosphate (GS4104 or Tamiflu®), which is converted in the liver to oseltamivir carboxylate GS4071, the active drug.

f07-23-9780723434337

References in context

  • Zanamivir and oseltamivir are analogues of sialic acid, as shown in Figure 23.2 These compounds specifically inhibit all nine NA subtypes in nature, including the subtypes contained in the avian strains of influenza A H5N1, H7N7 and H9N2 that have infected humans (see also Chapter 3).
    Go to context

References

Label Authors Title Source Year
1

References in context

  • Amantadine and rimantadine were the first generation of influenza antiviral agents.1 These compounds specifically block the ion channel function of the M2 protein of influenza A virus (see Chapter 2), thus interfering with corresponding specific steps in the viral life cycle.
    Go to context

  • Particularly in the elderly or those with renal failure, serious CNS side effects due to amantadine (and less often rimantadine) include confusion, disorientation, mood alterations, memory disturbances, delusions, nightmares, ataxia, tremors, seizures, coma, acute psychosis, slurred speech, visual disturbances, delirium, oculogyric episodes and hallucinations.1 Amantadine causes CNS side effects in about 15–30% of people, as well as dose-related abnormalities in psychomotor testing.
    Go to context

  • Emergence of resistant virus does not appear to cause a rebound in illness in immunocompetent adults, but may be associated with protracted illness and shedding in immunocompromised hosts.22 Importantly, resistant virus can be spread to others and has caused failures of antiviral prophylaxis under close contact conditions, as in nursing homes23 and households.1 The resistant viruses appear to retain wild-type pathogenicity and cause an influenza illness indistinguishable from that caused by susceptible strains.
    Go to context

FG Hayden, FY Aoki. Amantadine, rimantadine, and related agents. SL Barriere (Ed.) Antimicrobial Therapy and Vaccines (Williams & Wilkins, Baltimore, 1999) (1344 - 1365) 1999
2

References in context

  • The neuraminidase inhibitors are novel drugs, designed on the basis of the three-dimensional structure of the influenza A and B neuraminidase2 (see Chapter 2).
    Go to context

  • Zanamivir and oseltamivir are analogues of sialic acid, as shown in Figure 23.2 These compounds specifically inhibit all nine NA subtypes in nature, including the subtypes contained in the avian strains of influenza A H5N1, H7N7 and H9N2 that have infected humans (see also Chapter 3).
    Go to context

  • Zanamivir and oseltamivir are analogues of sialic acid, as shown in Figure 23.2 These compounds specifically inhibit all nine NA subtypes in nature, including the subtypes contained in the avian strains of influenza A H5N1, H7N7 and H9N2 that have infected humans (see also Chapter 3).
    Go to context

  • The inhibition of neuraminidase on both influenza A and B viruses has three important consequences.2 First, it hinders the passage of the virus through the mucus of the respiratory tract and thus retards initial infection of epithelial cells.
    Go to context

PM Colman. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Crossref. Protein Sci 3 (1994) (1687 - 1696) 1994
3

References in context

  • At low, pharmacologically relevant concentrations (<0.75 µg/ml), amantadine and rimantadine specifically inhibit the ion channel activity of the M2 protein, probably through direct binding to the pore region of the protein.3 In doing so, the drugs inhibit acidification of the interior of susceptible viruses and dissociation of the M1 protein from the viral nucleocapsid (Figure 22), which is a necessary step in the uncoating of the viral genome during infection (see Chapter 2).
    Go to context

C Wang, K Takeuchi, LH Pinto, RA Lamb. Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J Virol 67 (1993) (5585 - 5594) 1993
4

References in context

  • In addition, within the infected cell, M2 protects newly synthesized HA against premature exposure to low pH by transiently neutralizing the pH of the trans-Golgi network, while HA is in transit to the cell surface.4 Amantadine and rimantadine counteract this protection and thus indirectly induce a premature conformational change in HA, inactivating the protein (Figure 22).
    Go to context

RW Ruigrok, EM Hirst, AJ Hay. The specific inhibition of influenza A virus maturation by amantadine: an electron microscopic examination. Crossref. J Gen Virol 72 (1991) (191 - 194) 1991

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