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1)Target sites :
HA :
-exmple :
- human monoclonal IgGI antibody
-neutralising virus
- spesifically bind to HA & internalized together with virus
- pH drop at late endosome, antibody remain bound to a highly conserved epitope located in stem of HA.
-Antibodies block conformational change of HA
-preventing viral fusion & infection.
NA -
- example : Oseltavimir
- Oseltavimir inhibit neuraminidase
- The enzyme cannot break the bond between newly produce virion & the host cell membrane.
- no new virus produced
M2 -
-example : Amantadine
- amantadine and rimantadine (M2 proton channel blockers) the M2 proton channel blockers elicit pharmacological activity through destabilizing the helices by blocking the proton transport across the transmembrane.
2) - The virus constantly changing
- To one season's strain does not translate into immunity in subsequent years.

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1) Target sites for influenza treatment
HA, NA (Encapsidates the viral RNA and participates in the infectious life cycle of virus), M1, NEP, NP, PA, PB1, PB2

2) Mechanism for each target sites
HA (The hemagglutinin mediates attachment of the virus particles to the respiratory epithelial cells via specific receptors. Once the virus has bound to its host cell, it is transported into the cytoplasm in an endosome. The acid pH in the endosome activates or opens an ion channel called the M2 protein, permitting hydrogen ions to enter the virion. The resulting acidification of the virus is necessary for viral uncoating, another essential step in viral replication. Amantadine inhibits the function of the M2 protein and thus stops the replication process.)

NA (The NAI drugs, zanamivir and oseltamivir, bind to the active site on the viral neuraminidase, blocking its activity. Thus, virus particles cannot exit the cells as easily, and they tend to clump and not disperse. This impedes their ability to infect more cells and attenuates the patient's infection).

3) Reason of new vaccine be developed every year.
antigenic drift-process of genetic based antigen change in flu strain; viral genomes constantly mutate-producing new antigens; new forms of antigens that are sufficiently different from old antigens will no longer bind to antibody receptors; viruses with new antigens evade immunity; people lose immunity to new strain; vaccines against original antigen become less effective

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The target site is the Matrix 2 (M2) and Neuraminidase (NA) protein.
For NA, the example is oseltamivir which is a neuraminidase inhibitor, a competitive inhibitor of influenza's neuraminidase enzyme. The enzyme cleave the sialic acid which is found on glycoprotein on the surface of human cell that helps new virions to exit the cell. Thus, oseltamivir will prevent new virus particle from being released.
For M2, the example is Amantadine which is function in mechanistically identical fashion in entering the barrel of tetrmeric M2 channel and blocking the pore function. Resistance to the drug class is a consequence of mutations to the pore lining residues of the channel , leading to the inability of the sterically bulky adamantine ring that both amantadine and remantadine share, in entering in their usual way into the channel.
The reason why new vaccine must be developed every year because the influenza virus is changing all the time at swift pace. Since the influenza virus mutate so quickly it evades the vaccine. Vaccine and immunity one year do not necessarily provide protection the following year.

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1.)
Target Sites: HA
Mechanism: Antibodies block the confirmational change of HA, preventing viral fusion & infection :)
Target Site : Admantane-based M2
Mechanism : The replication of influenza A viruses needs a pH-gated proton channel (M2 channel). Thus, it inhibit the M2 channel
Target Site : Epithelial cell surface
Mechanism : use of sialidases, which remove sialic acid from the epithelial cell surface and cause prohibit of the virus uptake in target cell

2.)
The virus cell will be continue mutating like the stain H74 mutation.therefore new generations of NA inhibitors should have both excellent activity against resistant strains and improved oral bioavailability.

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1) Target site of influenza virus treatment is HA,NA,M2
Mechanism:
- HA
-the antibodies bind to HA and internalized together with virus
-when pH drop in late endosome the antibodies remain bind to highly conserve epitope lacated in HA
-antibodies blocked the confirmational changes of HA and prevent viral fusion and infection
-the trapped virus will degrade. Then leaving the cell

-NA (neuraminidase)
-important for the efficient release of newly produced viruses

-M2 ion
- promotes viral structure change during cellular entry

QUESTION 2
-the influenza virus is changing all the times.
-since the influeza virus mutates so quickly, it evades the vaccines.
-vaccines and immunity for a year do not necessary provide protection the following year
-to develop vaccines that will last throughout of the lives.
-it is concerned about the triggering of immune response. For example bringing about specific action from our immune systems
-next, The vaccine cannot be prepare beforehand because no one knows what kind of virus will strike
-the influenza virus changes its genetic makeup every Year

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1) The target sites for the influenza virus treatment is the monoclonal antibodies will bind at the outer membrane of  Hemeagglutinin Protein (HA) when it undergoes endocytosis, forming endosomes. The antibodies will block HA protein which functions as facilitate the virus binding to the siallic acid and subsequently for virus fusion.

HA consists of 2 parts: HA 1 and HA2

Meanwhile, the membrane envelop as well contains M2 Ion Channel which promotes virus structural changes during cellular entry.

The Neuraminidase protein (NA) releases newly produced viruses, as the influenza virus consist of 8 segments that will make it way to the cell nucleus.

The mechanism of virus infection could not occur if there is no proteolytic cleavage enzyme (from host cell)  which will bind to HA
2) Viral genome will constantly mutate in which producing new antigens that are sufficiently different from the previous antigen.
Thus, antibody will no longer able to bind the new  receptors of virus.
This means infected people will lose immunity to new strains: which make previous vaccine (that aims old antigen)  become ineffective.

That is why pharmaceutical companies need to develop new vaccine every year.  🔬

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Suruthi Kavesha Hemalah Jamuna Tharishini 

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Suruthi Kavesha Hemalah Jamuna Tharishini 

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Target site: HA
Antibodies bind to HA and internalized together with virus. Antibodies block the conformational change of HA by preventing viral fusion and infection

Target site: NA (neuraminidase)
NA inhibitor used to interfere with hemagglutinin binding to sialic acid receptor.NA inhibitors mimic SA stucture in its transition state during NA catalyzed hydrolysis, represent a class of anti influenza drug with broad activities against different influenza virus strain.

Target site : M2 ion channel protein
M2 ion channel blockers bind to interior of ion channel, block the influx of proton and prevent hemagglutinin mediated membrane fusion. The proton blocking effect may result from electrostatic repulsion potential from charge amino group.

Target site: NP
NP- based anti-viral drug development target on NP interaction with virus RNA and block formation of vRNPs by mechanisms of NP oligomerization.

Pharmaceutical companies develop new vaccine every year because many strains of flu virus determine every year and the new strains will arise in each year or change due to various mutations and other characteristic, the previous serum become ineffective and useless and changes in its genetic makeup.

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1) The target site for influenza virus treatment is at HA site, NP site, M2 site, NA site
- for the HA site, they targeted by preventing the attachment of the virus to the receptor through the prevention of protease to HA, this will eventually prevent the fusion with the endosome membrane upon endocytosis resulting the degradation of the virus
- M2 is targeted where the activity of transferring proton into interior of the virion is inhibited
- NA inhibition is through the binding of the NA to the mimic SA structure of the antiviral
- NP will resulting the modification of the polymerase for unprime initiation, antiviral will target this protein by substitute a single amino acid in the tail loop to eliminate oligomerization.

2) Vaccine must be develop every year because they are easily mutated, the vaccine are complex product and the science of vaccinology are difficult, there are many other infectious diseases cannot yet be vaccinated against, and these still cause widespread illness, disability and death.
- to make money

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1. The target site for influenza virus treatment is  hemaglutinin protein (HA), neuraminidase (NA), and M2 ion channel.

In HA target site, the antibodies will bind to the HA site and internalized together with the virus. The antibodies then will block the conformational changes of HA by preventing viral fusion and infection.

In NA target site, the influenza virus induced long term and cross protective immunity.

For M2 ion channel protein target site, M2 ion channel blockers bind to interior of ion channel, block the influx of proton and prevent hemaglutinin mediated membrane fusion. The proton blocking effect may result from electrostatic repulsion potential from charge amino acid.

2.The antigenic structures of the HAs of both influenza A and B viruses undergo antigenic drift, which results from the selection of mutant viruses that evade antibodies directed against the predominant antigenic type of the HA circulating in the human population. Mutant viruses are readily generated because the viral RNA polymerase has no proof-reading function. Because of antigenic drift, the vaccine has to be reformulated each year (Robert, Krug, and James, 2010)

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1. A) target site: HA protein of the virus
How: crucell antibody binds specifically to HA binding site and internalize together with the virus (endosome)
-pH drops in late endosome, antibody remains bound to a highly conserved epitope located in the stem of HA.
-antibody block the conformational changes of HA by preventing viral fusion and infection.
-trapped virus degraded,leaving cell unharmed.

Some of crucell new antibodies can also prevent the initial cleavage of HA.
-they bind to a highly conserved epitope close to the HA cleavage site, by preventing the host proteases from activating the virus.
-the uncleaved virus is not infectious to the cell.

2. Target site: NA
How: in vitro, by carboxyclic compound (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexane-1-carboxylic acid that competitively inhibits NA by incorporating lipophilic side chain in the molecule that produces hydrophobic pockets at NA's Active site.

3. Target site: M2 ion channel protein & NA
How: by amantadine & rimantadine that targets the m2 ion channel protein. NA undergoes antigenic changes on their glycoprotein due to antigenic drift.