Antivirals

Question 1

What are onsiderations for drug development

Answer 1

• Expense vs need vs resistance
• burden of disease and clinical need
• understanding virology: whar to target
• Drug development: screening compounds or drug design
• Clinical trials and impact: adverse effects and monitoring of resistance

Question 2

What are 3 types of influenza virus

Answer 2

Three types Influenza A –Multiple host species e.g. birds
–Antigenic drift and shift: slowly changes coat from year to year. Sometimes a huge change can lead to a new virus which can cause a pandemic

Influenza B –No animal reservoir –Lower mortality
- outbreak every 3 or 4 years

Influenza C –Common cold like

Question 3

What are influenza related complications

Answer 3

Most complications occur in otherwise healthy persons since it affects everyone everywhere every year
– Bronchitis, pneumonia
– Sinusitis
– Exacerbation of underlying disease e.g. DM, kidney disease, HF

Question 4

What are the treatments for influenza related complications

Answer 4

|60%-80% of patients with complications receive antibiotics

Antibiotics prescribed for |30%-45% of patients presenting with influenza or ILI

Question 5

Describe teh structure of influenza A virus

Answer 5

Flu - 7 rna segments . Protein envelope, capsid to protect. Around surfact another layer made out of fats and lipids to attach to human host cells. Proteins stic out - virulence factors - this is hemagglutinini in influenza a

Question 6

Describe the life cycle of influenza virus

Answer 6

Glycoproteins receptor (hemaglutinign) on upper resp cells recognises Sialic acid on virus
- Virus sticks there.. once attached, then invades the host cell to replicate.
- Goes into cell in vesicle and breaks up Ito viral nucleic acid segments
- produces new parts of virus thru transcription and translation - - These are then excreted out of cell - goes on to produce ongoing infection.
If you block haemaglutinin , virus wont stick to cell
- Influenze vaccine contains hemagluttinin - antibody. Can target any point of virus life cycle . Eg at point when it leaves cell - neuraminidase inhibitor

Question 7

What is the role of hte M2 channel in virus replication?

Answer 7

The M2 ion channel allows H+ into it. If the centre of the cell is acidic, viral capsid of a virus is removed, leading to the release of the viral genomic nucleic acid.
IF this channel can be blocked, then virus replication can be blocked.

Question 8

What are Amantadanes?

Answer 8

Amantadine and rimantadine are active against influenza A. They are tricyclic primary animes which block the M2 channel to inhibit viral uncoating
Also has anti-parkinsonism activity

Question 9

What are the limitations of M2 inhibitors?

Answer 9

• Work on influenza A only
• Have CNS and renal side effects
• A single point mutation in M2 gene S31N can stop the drug from working. 31N amino acid change alters the binding site: drug no longer binds and blocks channel function

Question 10

How can m2 inhibitors be designed

Answer 10

The structure of a possible target, or binding of an existing compound can be used to evaluate and design new drugs
– Gene sequencing of protein
– X-ray crystallography
– Nuclear Magnetic Resonance Sits inpcket - ring binds

Question 11

What is neuraminidase

Answer 11

Novel antiviral target: neuraminidase
Neuraminidase essential for virus replication Surface of influenza highly variable but NA active site is conserved across subtypes –Human and non-human influenza A –Influenza B –M2 resistant viruses –Avian strains including H5N1 –Reconstructed 1918 pandemic H1N1

Question 12

What is the role of neuraminidase in influenza?

Answer 12

NA cleaves haemagglutinin which releases the virus from the celll surface. If NA is inhibited tehn the virus is stuck

Question 13

What is the role of a neuraminidase inhibitor

Answer 13

Can no longer releasedvirus from cell. Neuraminidase inhibitor - circus stuck there - not leaving the membrane - cant spread th infection . Stop them being releas

Question 14

Gove some examples of neuraminidase inhibirots

Answer 14

Zanamavir

Oseltamivir

Question 15

What are the actions of zanamavir and oseltamivir

Answer 15

Zanamavir:Prodrug that when activated, inhibits viral neuraminidase (glycoprotein enzymes on viral surface). By doing so, entry into uninfected cells and budding from infected cells is prevented. Hemagglutinin and sialic acid bond can’t be broken.
Oseltamivir: same as above but not a prodrug

Question 16

What are the guidelemines for use of neuraminidase inhibirtos?

Answer 16

There was resisitance.
Cochrane review: concluded no value
PHE guidance UK Primary care: only when CMO letter confirms presence of circulating seasonal influenza – Healthy people: no Rx unless ptfelt to be at risk – At risk (inc preg): oseltamivir asap (no need for confirmation) – Severely immunosuppressed: oseltamivir

Primary care: only when CMO letter confirms presence of circulating seasonal influenza – Healthy people: no Rx unless ptfelt to be at risk – At risk (inc preg): oseltamivir asap (no need for confirmation) – Severely immunosuppressed: oseltamivir or inhaled zanamivir (espif H1N1) Secondary care: use oseltamivir in suspected or confirmed flu – If H1N1 (higher risk of oseltamivir resistance) circulating, consider zanamivirespecially in severely immunosuppressed: zanamivirinhaled ( nebuliser or IV if can’t take inhaler-but ?not licenced or available)
or inhaled zanamivir (espif H1N1) Secondary care: use oseltamivir in suspected or confirmed flu – If H1N1 (higher risk of oseltamivir resistance) circulating, consider zanamivirespecially in severely immunosuppressed: zanamivirinhaled ( nebuliser or IV if can’t take inhaler-but ?not licenced or available)
Every year 8 week period where flu active - surveillance program that detects starter flu program - when first isolate - then big peaks in influenza activity. When flue circulating in uk - if people pressing with influenza like symptoms, use neutominidase - just i they are at risk

Question 17

What is human herpes virus?

Answer 17

Large family c150 species DNA viruses Widespread across animal kingdom High rates of infection in human population Generally mild primary infection Establish latent infection Secondary infection/reactivation

Question 18

Describe the sturucture of herpes virus

Answer 18

ss

Question 19

What is the treatment for HSV?

Answer 19

Specific antiviral therapy Supportive care
– Bacterial complications

Nucleoside analogues inhibiting herpes viral DNA polymerase
– Aciclovir and valaciclovir (HSV, VZV)
– Cidofovir (CMV, resistant HSV)
– Ganciclovir (CMV, EBV

Question 20

Describe hsv-1 replicatuon

Answer 20

-

Question 21

What is acyclovir used in

Answer 21

HSV-1 + HSV-2 infections
Chickenpox - topical use to reduce severity of skin lesions
Shingles - oral antivirals to reduce pain and accelerate healing of blisters

Question 22

What is the moa of acyclovir?

Answer 22

Prodrug that is converted into a guanosine analogue (acyclovir triphosphate). Once incorporated, it inhibits viral DNA polymerase (acting as chain terminator).

Question 23

What are valacyclovir and valgancyclovir

Answer 23

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