Antiviral Drugs

Question 1

How are viruses classified?

Answer 1

• Type and structure of nucleic acid and the strategy of its replication.
• Symmetry of capsid.
• Presence or absence of lipid membrane

Question 2

What are the stages un viral life cycle?

Answer 2

1) Attachment
2) Penetration
3) Disassembly (release of viral genome),
4) Transcription
5) Translation
6) Replication
7) Assembly
8) Release

Question 3

Name and describe the three mechanisms of antivirals

Answer 3

Virucides - These directly inactivate viruses eg, detergents, UV light, cryotherapy.

Antivirals - Inhibit replication at cellular level but therefore aren’t effective in elimination of nonreplicating viruses.

Immunomodulators - Replace deficient host response or enhance endogenous response

Question 4

Describe some of the targets for antiviral drugs

Answer 4

• Entry inhibition,
• Viral disassembly,
• Viral replication (Viral polymerases, viral proteases, integrase),
• Viral release inhibitors

Question 5

What is the function of nucleotide analogues?

Answer 5

The competitively inhibit the action of viral polymerase which inhibits new viral DNA production

Question 6

Describe features of retroviruses

Answer 6

• Positive sense single stranded RNA virus.
• Need for reverse transcriptase to make DNA copy of viral RNA. The DNA copy is then integrated into the genome of host cell and terminated as provirus. The provirus DNA is then transcribed into new genomic RNA and mRNA for translation into viral proteins.

Question 7

Describe the process of HIV entry

Answer 7

It is mediated by envelope glycoprotein spike (mainly gp120) which binds to a CD4 receptor and one of the two co-receptors CCR5 or CXCR4

Question 8

What is the significance of CCR5 co-receptor

Answer 8

A mutation in this receptor has resulted in HIV being unable to bind to cells. Therefore this is a good target for treatment.

Question 9

Give examples of entry inhibitors

Answer 9

• Fusion inhibitors eg, Enfurvitide (T20) (not used often as it is toxic) prevents the viral cells from fusing with host cell and releasing viral genome.
• CCR5 antagonists, eg, Maraviroc

Question 10

What are the two reverse transcriptase inhibitors?

Answer 10

• Reverse transcriptase inhibitor .

- Non-Nucleoside reverse transcriptase inhibitors

Question 11

Name some drugs in the nucleotide reverse transcriptase inhibitors (NRTIs) and their side effects

Answer 11

Abacavir (analogue of guanosine) - SE = ischaemic heart disease

Tenofovir (Analogue of adenosine) - SE = Decreased bone mass density, osteomalacia, increased fracture risk

(Emtricitabine and lamivudine)

Question 12

NRTIs are prodrugs, what is needed to activate them?

Answer 12

Phosphorylation by viral and/or cellular kinase.

Question 13

Name two examples of NNRTIs

Answer 13

Efavirenz
Rilpivirine
Both drugs can cause neurological and psychiatric AE.

Question 14

Describe the mechanism of HIV protease inhibitors

Answer 14

Virus specific protease gives rise to various functional proteins and since the protease doesn’t exist in host it is selective.

Question 15

Name some examples of protease inhibitors and their side effects

Answer 15

Darunavir (ischaemic heart disease and nephrolithiasis) , Atazanavir (nephrolithiasis)

Question 16

What is the mechanism of integrase inhibitors

Answer 16

Inhibit HIV integrase activity:

• 3’ end processing of double stranded viral DNA
• Strand transfer which joins viral DNA to host chromosomal DNA forming a provirus

Question 17

Name an example of an integrase inhibitor and its side effects

Answer 17

Dolutegravir - weight gain, depression and suicidal ideation

Question 18

What is HAART?

Answer 18

Combination therapy - typically 2 NRTIs and an additional drug from another class

Question 19

Describe how RNA viruses are classified?

Answer 19

Positive-sense viral RNA (can be imnmediately translated by host cell)

Negative-sense viral RNA - must be concerted to positive-sense by RNA dependant RNA polymerase.

Question 20

What are the three types of RNA genome?

Answer 20

dsRNA (double stranded), +ssRNA and -ssRNA. (+/- single stranded)

Question 21

Describe features of hepatitis C virus

Answer 21

Positive-sense single stranded RNA virus which can cause acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma.

Question 22

Name targets of HCV treatment and examples of drugs.

Answer 22

NS3 - Protease inhibitors, eg, simeprevir and grazorprevir.

NS5A - NS5A inhibitors eg, ledipasvir and elbasvir.

NS5B - Nucleotide inhibitors and non-nucleoside inhibitors eg, Sofosbuvir and Dasabuvir

Question 23

Describe features of Influenza

Answer 23

(Orthomyxoviridae). There are 3 types; A,B and C. They are enveloped negative-sense single stranded RNA virus.

Question 24

What is the function of neuraminidase inhibitors in the treatment for influenza

Answer 24

Prevents the release of new viral cells

Question 25

Describe the mechanisms of another influenza antiviral treatments.

Answer 25

Amantadine/rimantadine - They block the M2 ion channel. (Concentrated in lysosomes0

Baloxavir - inhibits viral mRNA replication

Question 26

What are the functions of the M2 ion channel

Answer 26

• Virion uncoating following entry by endocytosis and

- Maturation of viral envelope proteins during virus assembly and release.

Question 27

Describe features of DNA viruses?

Answer 27

They use cellular enzymes for transcription and replication of their genome. Early mRNA transcripts = regulatory proteins and proteins for DNA replication. Late = structural proteins. eg, herpes simplex virus, human papilloma virus, Varicella zoster and hepatitis B virus.

Question 28

What is the mechanism and uses of Aciclovir

Answer 28

Deoxyguanosine analogue which competitively inhibits viral DNA polymerase. It is used in the treatment herpes simplex virus and varicella zoaster virus infections

Question 29

What are some other herpesvirus antivirals?

Answer 29

Valaciclovir - prodrug of aciclovir (higher oral bioavailability).

Ganciclovir - Deoxyguanosine analogue. It is an inhibitor of CMV replication.

Foscarnet - Directly inhibits herpesvirus DNA polymerase or HIV RT.

Question 30

describe some features of the hepatitis B virus

Answer 30

• Enveloped, dsDNA virus which causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma.

Question 31

Describe the treatment of chronic HBV

Answer 31

Immunomodulatory using pegylated interferon alpha.

Nucleotide therapies - these are agents active against reverse transcriptase eg, tenofovir and entecavir.

Question 32

What is the development of resistance favoured by?

Answer 32

High viral load, High intrinsic viral mutation rate, degree of selective drug pressure and antiviral target that can mutate without affecting fitness.