Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against influenza.

    • "Influenza Virus Infection"¹⁰

      Attribution: Bertozzi C   "Influenza Virus Infection" https://www.youtube.com/watch?v=dAlyrR7seXA (11/2013) iBiology YouTube Channel:  https://www.youtube.com/channel/UCimxROEIlNsiRqT9X5tg2XQ

    • Neuraminidase Inhibitors

      • Introduction⁴

        • As described earlier, influenza viruses are enveloped RNA viruses of the Orthomyxoviridae family.⁴ 

          • The influenza viral genome is characterized by eight single-stranded, negative-sense RNA molecules that encode for 10 viral proteins.

            • RNA segments present in the virion are associated with the nucleoprotein (NP) and three viral polymerase subunits (PA, PB1, and PB2) forming the ribonucleoprotein complex (RNP).

            • The virion also contains the M2 ion channel protein in the viral nuclear export protein.

            • The only non-structural influenza A viral protein included is NS1 which functions in viral replication and host immune response modulation.

        • Antigenic differences in the NP protein and M proteins provide the basis of influenza virus classification (types A, B, C).⁴ 

          • Influenza A viruses are subtyped further on the basis of antigenic differences in surface glycoproteins, extending from the viral envelope, the hemagglutinin glycoprotein (HA) and NA (neuraminidase).

            • At least 16 HA subtypes and 9 NA subtypes of influenza a viruses have been described.

          • The hemagglutinin glycoprotein, HA, is both the most important antigenic determinant targeted by neutralizing antibodies and is essential for infection initiation.

          • The role of hemagglutinin, HA, in the initiation of infection is defined by its attachment to host cell receptors that express terminal sialic acid (SA) residues.

            • This process enhances viral entry into host cells.

            • HA has important binding site affinity for the linkage between those host cell surface receptors expressing terminal sialic acid residues and galactose in host cell receptors.

              • Human influenza viruses exhibit greater specificity to sialic acid residues linked to galactose by α-2,6 linkages which differs from the preferred binding site for avian influenza virus.⁴

                • However bronchiolar and alveolar cells in the human lower respiratory tract may also contain avian α-2,3 linked SA receptors, possibly accounting for avian H5N1-mediated severe pneumonia in humans.^4,5,6  

              •  

                "Influenza Virus binding to cell surface glycoproteins with Neu5Ac"⁷

                Figure Attribution:  Adapted from reference 7 (Jakubowski H http://employees.csbsju.edu/hjakubowski/classes/ch125/IB4_IMF_Carbohydrates.html ) (O- or N-substituted neuraminic acid derivative are collectively named sialic acids, with the major mammalian cellular form being N-acetylneuraminic acid.)

              •  

                Tamiflu (Oseltamivir phosphate) and Relenza (Zanamivir)⁹

                Attribution:  Bertozzi C Tamiflu and Relenza https://www.youtube.com/watch?v=R8V_UyV_sRc 11/2013 iBiology YouTube Channel:  https://www.youtube.com/channel/UCimxROEIlNsiRqT9X5tg2XQ

        • Binding between viral HA and host cell SA moieties is not only required for infection initiation but also prevents release and spread of progeny virions from infected cells at the end of the viral replication cycle, except for the activity of viral neuraminidase (NA).⁴ 

          •  

            Ribbon Diagram:  Neuraminidase⁸

            DeLucas L Neuraminidase Ribbon Diagram (NASA) "Shown here is a segmented representation of the neuraminidase inhibitor compound sitting inside a cave-like contour of the neuraminidase enzyme surface."8 http://commons.wikimedia.org/wiki/File:Neuraminidase_Ribbon_Diagram.jpg

          • Neuraminidase in the influenza viral replication cycle catalyzes the cleavage of sialic acid-galactose linkages thus eliminating receptors recognized by hemagglutinin (HA).

            • This effect prevents of newly formed virions from associating with infected cell surfaces and as a result promotes viral spread to other, non-infected cells.

              • Accordingly, neuraminidase (NA) has become an important pharmacological target for antiviral drugs to exploit.

              • Furthermore, such antiviral drugs may be widely effective against influenza A and B viruses since the neuraminidase catalytic site is highly conserved i.e. is highly similar across viral isolates.⁴