Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against influenza.

    • Amantadine and Rimantadine

      • Introduction: 

        • Amantadine (Symmetrel) and an associated drug, rimantadine (Flumadine), the α-methyl derivative of rimantadine are both tricyclic amines.¹ 

        •  

          Amantadine (Symmetrel)

        •  

          Rimantadine (Flumadine) [α-methyl derivative of rimantadine]

           

        • These agents inhibit influenza A viral replication with rimantadine generally being up to 10 times more active compared to amantadine.¹

          • Rimantadine also exhibits inhibition for a causative agent of African sleeping sickness, Trypanosoma brucei.

        • The efficacy of amantadine or rimantadine is dependent on possible resistance of the influenza strain.¹ 

          • For example, nearly all strains of influenza A H1N1 (2008-2009 influenza season) were resistant oseltamivir (neuraminidase inhibitor).

            • Most of the 2009 H1N1 "swine" isolate, however, were susceptible to oseltamivir but this viral isolate exhibit resistance to amantadine and rimantadine.¹

              •  

                Swine Flu: Example of Antigenic Shift

                Mouagip (derivative work):  Illustration of Antigenic Shift (National Institute of Allergy and Infectious Diseases) http://commons.wikimedia.org/wiki/File:AntigenicShift_HiRes_vector.svg

              • Earlier, resistance to amantadine and rimantadine was noted in influenza A/H3N2 viruses during the 2005-2006 influenza season, also seen in the strain in 2008-2009.² 

                • Pandemic A/H1N1 viruses in 2009-2010 also exhibit resistance to both agents.

                  • As a result, these drugs are not typically recommended for clinical use unless the particular influenza A isolate is known to exhibit sensitivity.² 

                    • In that case, amantadine/rimantadine might be viewed as an option.

                • Amantadine and rimantadine appear effective in influenza A prophylaxis based on "large-scale" clinical studies of young adults and smaller studies involving children and the elderly.

                  • Using these agents to prevent influenza-like disease was associated with efficacy rates of about 55-80%. Higher rates were noted when virus-specific "attack rates" were computed.²

      • Mechanism of Action:  Amantadine and Rimantadine

        • Amantadine and rimantadine exhibit two mechanisms accounting for their antiviral effects.

          • These agents inhibit an early step in viral replication most likely related to viral uncoating.¹ 

            • This finding was suggested by Davies and associates who identified amantadine as an agent producing dose-related inhibition of influenza infection in three systems: tissue culture, chick embryos and mice.⁷ 

            • It was concluded that the agent at least in part acted by interfering with penetration of the host cell by the virus.⁷  

            • The amantadine effect of inhibiting viral uncoating is shared by rimantadine.⁸

            • Other structurally-related compounds such as benzyl-substituted amantadine derivatives, also classified as viral uncoating inhibitors have also been identified.⁹ 

          • Inhibition of Viral Uncoating¹⁰

            • As described earlier, amantadine's antiviral activity was first and generally described in 1964 (7).

              • Amantadine was later found to target specifically the M2 influenza A viral protein and affecting its antiviral activity at that site.

                • Rimantadine acts similarly.

                • These drugs are part of a general class, adamantanes.

              • Influenza A viral isolates resistant to amantadine and rimantadine which renders these drugs ineffective results from a single amino acid change in the M2 protein, given that this alteration appears to have no or limited effect on viral activity.

              • Newer agents (9) are in development that can block both adamantane-sensitive and-resistant isolates.

            • The M2 protein plays a crucial role in the release of viral ribonucleoprotein complexes into the cytoplasm.¹⁰ 

              • This process involves influenza A virus uncoating, which is defined by a fusion of viral and endosomal membranes.

                • Two viral proteins, M1 and M2, are important in this process.¹⁰ 

                  • M1 is an important structural protein in the viral membrane and appears to link the viral membrane containing essential glycoproteins with viral ribonucleoproteins.

                    • The M1 protein can alter virion shape.

                  • During uncoating, M1 interactions with viral membrane and M1 interactions with viral ribonucleoproteins must be disrupted to permit complete uncoating and resultant ribonucleoprotein transport to the nucleus.

                  • This disruption requires viral protein M2.

                    • The M2 protein is an ion channel, the activity of which is pH dependent.

                    • At lower pH the ion channel activity is enhanced; upon endosomal acidification, increased M2-dependent proton (H⁺) translocation from the endosome into the virion occurs.

                    • This proton movement results in an acidification internal to the virus particle and this acidification (decrease in pH) promotes dissociation between M1 and viral ribonucleoproteins.

                    • This dissociation allows for release of the viral ribonucleoprotein complexes into the cytoplasm.

                     

                    • Amantadine-Mediated Blockade of the Endosomal Acidification Step in the Influenza A Virus Replication Sequence

                      Figure Attribution:  Adapted from "Release of influenza viral RNAs into Cells (6 May 2009)12.  Racaniello V:  Virology blog about viruses and viral disease http://www.virology.ws/2009/05/06/release-of-influenza-viral-rnas-into-cells/ 12

                    • Accordingly, blockade of the M2 channel by e.g. amantadine or rimantadine is sufficient to block this step and confers the antiviral activity associated with these drugs.

                      •  

                        Influenza A virus M2 protein ion channel in complex with amantadine¹¹

                        Structure of the influenza A virus M2 protein ion channel in complex with amantadine. Attribution:  This figure is part of Figure 1 (Fig. 1 A) of  reference 11.

                      • As noted earlier however, a mutation, even a single mutation, in the M2 channel protein may be sufficient to confer resistance of the virus to the adamantane effects.¹⁰

          • These agents also affect a late step in viral assembly, related to hemagglutinin processing.¹