PS01 - Antiviral Agents

Question 1

What are the six stages of viral replication?

Answer 1

Attachment
Entry
Uncoating
Macromolecular Synthesis
Assembly
Release

Question 2

What is the MoA of Aciclovir?

Answer 2

Aciclovir is an analogue of Deoxyguanosine, but without a 3’ hydroxyl group
Both a 5’ and a 3’ hydroxyl group are required for the replication of DNA
Without the 3’ group DNA synthesis comes to a halt

Question 3

How is Aciclovir selectively toxic?

Answer 3

Aciclovir has to be triphosphorylated to have its DNA chain termination effect
The initial phosphorylation is performed by HSV-TK (thymidine kinase)
HSV-TK is present in viral cells but not eukaryotic cells

Question 4

What determines the cellular uptake of Aciclovir into specifically viral cells?

Answer 4

Diffusion down a concentration gradient

Question 5

What three factors determine the selective toxicity of Aciclovir?

Answer 5

Only active in viral cells (HSV-TK)
Concentrated in viral cells
Higher affinity for viral DNA polymerase

Question 6

Describe the spectrum of activity of Aciclovir

Answer 6

Narrow, only targets HSV1/2 and VZV

Only these families possess HSV-TK

Question 7

How does resistance to Aciclovir arise?

Answer 7

Absence of Thymidine Kinase (TK-ve)
Alteration of Thymidine Kinase
Exist pretreatment, appear during therapy
Alteration of DNA polymerase

Question 8

Why is Aciclovir resistance due to TK absence not a clinical issue?

Answer 8

Because the absence of HSV-TK renders the variants non-pathogenic
Alteration strains are also attenuated

Question 9

What Aciclovir resistance mechanism is clinically important?

Answer 9

Alteration of DNA polymerase, strain is fully virulent

Question 10

In what population is Aciclovir resistance a huge clinical problem?

Answer 10

AIDS patients suffering from repeated HZV infections

Question 11

What is Valaciclovir?

Answer 11

A variant of aciclovir joined to a valine ester

Question 12

What is the key property of Valaciclovir?

Answer 12

Valaciclovir has a much higher oral bioavailability than aciclovir

Question 13

What is Penciclovir?

Answer 13

An antiviral agent which acts as a viral DNA polymerase inhibitor but is not a chain terminator

Question 14

How does primary oral herpes present?

Answer 14

Painful, white lesions on the tongue and soft/hard palate

Question 15

Where does herpes virus lie dormant?

Answer 15

Trigeminal ganglion

Question 16

How does recurrent oral herpes present?

Answer 16

Cold sores

Question 17

In what situation is treatment of oral herpes clinically justifiable?

Answer 17

Treatment of primary oral herpes ONLY

Question 18

How does primary genital herpes present?

Answer 18

Painful, white lesions on the genitalia

Question 19

How does recurrent genital herpes present?

Answer 19

Fewer, less painful lesions

Question 20

In what situation is treatment of genital herpes clinically justifiable?

Answer 20

Treatment of primary genital herpes

Prophylaxis for frequent, severe, atypical genital HSV

Question 21

How is treatment of atypical recurrent genital herpes managed?

Answer 21

Long term therapy

Titration of dose down to eventual cessation

Question 22

What is herpes simplex encephalitis?

Answer 22

Inflammation of the cerebral hemispheres due to infection with HSV

Question 23

How is herpes simplex encephalitis treated?

Answer 23

Immediate administration of i.v. aciclovir

Question 24

What other forms of HSV can be treated with Aciclovir?

Answer 24

Ocular herpes simplex

Eczema herpeticum

Question 25

What diseases are caused by Varicella Zoster Virus?

Answer 25

Chickenpox | Shingles

Question 26

When is Aciclovir used to treat chickenpox?

Answer 26

In adults, often suffering from Varicella Pneumonia (i.v. aciclovir)

Question 27

What complications can chickenpox cause in pregnancy?

Answer 27

Increases risk of varicella pneumonia

Question 28

Should aciclovir be used in pregnancy?

Answer 28

In life threatening situations ONLY | Worries of teratogenesis as DNA synthesis inhibitor but safe record

Question 29

Where does VZV go latent?

Answer 29

Nerve cell bodies in the spinal cord and cranial nerves

Question 30

How should reactivated VZV (shingles) be treated?

Answer 30

Immediately w/ i.v. aciclovir in immunocompromised and most other patients

Question 31

What is disseminated voster?

Answer 31

Unusually widespread herpes zoster in immunocompromised patients

Question 32

What is the main problem with Aciclovir/Aciclovir like drugs?

Answer 32

They have a very narrow spectrum of use

Question 33

Why can Aciclovir not be used in Cytomegalovirus?

Answer 33

CMV does not posses HSV-TK so cannot phosphorylate aciclovir

Question 34

What antiviral can be used to treat CMV?

Answer 34

Ganciclovir, a drug with a similar MoA to aciclovir but that is initially phosphorylated by UL97

Question 35

Against which herpesviruses is Ganciclovir active?

Answer 35

All herpesviruses

Question 36

What are the disadvantages of Ganciclovir?

Answer 36

Poorly absorbed orally (use valganciclovir) | Toxic, often in bone marrow (less selective for viral cells)

Question 37

What is Cidofovir?

Answer 37

An acyclic phosphanate nucleotide analogue used as an antiviral to treat CMV retinitis

Question 38

What is the MoA of Cidofovir?

Answer 38

Same as Aciclovir (DNA chain terminator) but with the first phosphate already added

Question 39

What is the disadvantage of Cidofovir?

Answer 39

Less selective for virally infected cells | Leads to greater toxicity (nephrotoxic)

Question 40

What is the advantage of Cidofovir?

Answer 40

Can inhibit any viral DNA polymerase (potentially)

Question 41

What is Adefovir?

Answer 41

An analogue of Cidofovir used to treat chronic Hep-B infection

Question 42

What is Foscarnet?

Answer 42

A pyrophosphate analogue used as an antiviral agent

Question 43

What is the MoA of Foscarnet?

Answer 43

Inhibits DNA polymerase as it forms phosphodiester linkages in the DNA chain

Question 44

What are the disadvantages of Foscarnet?

Answer 44

Poor oral availability | Nephrotoxic

Question 45

What are the three CMV antiviral agents?

Answer 45

Cidofovir Ganciclovir Foscarnet

Question 46

What is Ribavirin?

Answer 46

A nucleotide analogue used as an antiviral agent

Question 47

What is the MoA of Ribavirin?

Answer 47

Not entirely known Possibly interferes w/ mRNA processing Possibly acts as a mutagen

Question 48

For what viruses is Ribavirin effective?

Answer 48

Severe RSV infection (inhalation) Lassa fever Chronic hepatitis C (w/ IFN)

Question 49

How do Uncoating Inhibitors work?

Answer 49

They inhibit the uncoating of the viral nucleic acid from its protective nuclear capsid

Question 50

Give two examples of Uncoating Inhibitors

Answer 50

Amantadine | Rimantadine

Question 51

What viruses is Amantadine treatment effective for?

Answer 51

Influenza A only

Question 52

What is the MoA of Amantadine?

Answer 52

Amantadine acts to block an ion channel created by one of the matrix proteins of Influenza A, preventing uncoating

Question 53

What are the disadvantages of Amantadine treatment?

Answer 53

Only effective in Influenza A Poorly tolerated (CNS stimulation) Resistance rapidly emerges

Question 54

How does resistance to Amantadine arise?

Answer 54

A SNP in the matrix protein, preventing Amantadine binding

Question 55

What two glycoproteins are studded throughout the viral lipid envelope?

Answer 55

Haemagluttinin | Neuraminidase

Question 56

What is the function of Neuramindase?

Answer 56

Cleaves the glycosidic linkages of neuraminic acids, allowing for the release of virions from infected cells

Question 57

What is the MoA of Neuramindase Inhibitors?

Answer 57

Compounds that bind to the active site of Neuramindase and inhibit it, preventing the release of virions from infected cells

Question 58

Give two examples of Neuramindase Inhibitors

Answer 58

Zanamavir (inhaled) | Oseltamivir/Camiflu (oral)

Question 59

What are Neuraminidase Inhibitors used to treat?

Answer 59

Severe influenza infection | Influenza infection in high risk individuals

Question 60

What is the advantage of Neuraminidase Inhibitors?

Answer 60

Work against all known influenza NA

Question 61

In which strain of influenza has resistance to Neuraminidase Inhibitors been demonstrated?

Answer 61

H5N1 (avian) w/ H274Y mutation