Neuraminidase Inhibitors

Neuraminidase inhibitors are antiviral drugs used to treat acute respiratory infections and influenza (a highly contagious viral infection that affects the respiratory system and is a major cause of morbidity and mortality) Zanamivir is approved for treatment of uncomplicated acute illness caused by influenza virus in persons aged greater than or equal to 12 years who have been symptomatic for no more than 2 days.

1. Neuraminidase inhibitors JASERAH SYED MSc - I

2. INTRODUCTION Neuraminidase also called  sialidase,are a group of enzymes that cleave sialic acid, a carbohydrate occurring on the surfaces of cells in humans and other animals and also in plants and microorganisms.  These enzymes are known to occur as Ags  (foreign proteins that stimulate the production of  Abs ) on the surfaces of certain viruses, namely those of the families Orthomyxoviridae and Paramyxoviridae, as well as on the surfaces of some infectious bacteria and other microorganisms. Neuraminidase cleaves the sialic acid molecule, thereby freeing the virus to infect other cells in the host organism. Neuraminidase inhibitors inhibit the enzyme neuraminidase. They are commonly used as antiviral drugs because they block the function of viral neuraminidases of the influenza virus, by preventing its reproduction by budding from the host cell.

3. history The first Neuraminidase Inhibitors (NAIs) were synthesized in 1960s by Edmond et al . through an attempt to understand the catalytic mechanism of the neuraminidase enzyme. In early 1990s, the determination of biological crystal structure of influenza virus surface protein led to the discovery of the active site and provided the opportunities to discover and design new and specific inhibitors.

4. NAI- a key drug Influenza neuraminidase has been established as a key drug target for the treatment of influenza infections, predominantly for the following reasons: Firstly , the structure of the influenza neuraminidase active site is highly conserved between influenza A and B strains, making neuraminidase an attractive target for the development of broad-spectrum inhibitors (Yen et al. 2006). Secondly , resistance to neuraminidase inhibitors develops less commonly than to other anti-influenza drugs. Thirdly , in contrast to adamantanes, neuraminidase inhibitors are mostly well tolerated in patients under therapy. Finally , neuraminidase protein is a freely accessible target for antiviral molecules with an extracellular mode of action.

5. Difference between admantase and neuraminidase NEURAMINIDASE Effective against influenza A & influenza B Less toxic Effective against all subtypes of NA ADMANTASE Effective against only influenza A & not influenza B More toxic in comparison Not effective against all subtypes of NA

6. Mechanism of action The neuraminidase inhibitors Z anamivir and O seltamivir interfere with the release of progeny influenza virus from infected host cells, a process that prevents infection of new host cells and thereby halts the spread of infection in the respiratory tract. Since replication of influenza virus in the respiratory tract reaches its peak between 24 and 72 hours after the onset of the illness, drugs such as the neuraminidase inhibitors that act at the stage of viral replication must be administered as early as possible.

7. MECHANISM OF ACTION

8. SPECIFIC NA INHIBITORS Laninamivir Oseltamivir  (Tamiflu) Peramivir Zanamivir  (Relenza)

9. ZANAMIVIR MODE OF ACTION – Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others. It is also an inhibitor of influenza virus replication  in vitro  and  in vivo . In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.

10. OSELTAMIVIR MODE OF ACTION – Oseltamivir is a neuraminidase inhibitor, a competitive inhibitor of influenza´s neuraminidase  enzyme. The enzyme cleaves the  sialic acid which is found on glycoproteins on the surface of human cells, and helps new virions to exit them. Thus oseltamivir prevents new viral particles from being released.

11. PERAMIVIR MODE OF ACTION - Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.

12. USAGE There are 2 subgroups of NA inhibitors that have been approved by regulatory authorities in the US and Europe, Zanamivir and Oseltamivir . Both are for the treatment and prevention of influenza. Laninamivir Laninamivir is approved for the treatment of influenza.  Laninamivir is a long acting inhaled drug given as a prodrug . It is given as a single dose and remains active for at least 5 days and up to 7 days. Oseltamivir Oseltamivir can be found under trade names such as Antiflu , Fluvir , Fluhalt , , Omiflu , Rimivat , Virobin , Oseltamivir and Tamiflu.  Oseltamivir is used for patients 1 year and older. It is given as one dose, twice a day for the treatment of influenza. In the prevention of influenza, oseltamivir is given as one dose, once a day for at least 10 days after contacting with an infected person and up to six months . The most common side effects of Oseltamivir are headache and nausea (in adults) and vomiting, cough and nasal congestion (in children).

13. Peramivir Peramivir is approved for the treatment of influenza. It is used as intravenous and was used in the emergency treatment of 2009 H1N1 in select patients. Zanamivir Zanamivir is used for patients 5 years and older. It is given as one 10 mg dose, twice a day for the treatment of influenza. In the prevention of influenza, zanamivir is given as one 10 mg dose, once a day for 10 days after contacting with an infected person or up the 28 days. The most common side effect of Zanamivir is reported to be rash.