Antivirals (13.03.2020)

Question 1

Structure of a virus (4 main components)

Answer 1

• genetic material (RNA or DNA)
• capsid (protein shell surrounding the genetic material of the virus)
• lipid envelope (in more evolved viruses)
• envelope proteins (in more developed viruses)

Question 2

Distinguish between different types of virus and describe how they use the host cell to replicate

Answer 2

• HIV - Retrovirus, leukocytes
• Hepatitis - DNA & RNA viruses, hepatocytes
• Herpes Simplex - DNA virus
• Influenza - RNA virus

Question 3

Summarise viral hepatitis

Answer 3

• Tropism: Liver hepatocytes

- Hepatitis (Hep) B & C: Only chronic infection requires treatment

Question 4

Summarise the treatment for hepatitis B

Answer 4

Tenofovir -> nucleotide analogue, given sometimes with Peginterferon alfa
- treatment not cure (as soon as you stop tenofovir the virus comes back; Hep is a chronically managed disease but it is not cured by tenofovir)

Question 5

Summarise the treatment for hepatitis C

Answer 5

• Ribavirin & Peginterferon alfa
  Ribavirin -> nucleoside analogue prevents viral RNA synthesis
• Boceprevir -> protease inhibitor
  Most effective against Hep C genotype 1

Question 6

Describe the pharmacological treatment of different types of hepatitis:

Answer 6

A:

B: Tenofovir -> nucleotide analogue, given sometimes with Peginterferon alfa

C:

• Ribavirin & Peginterferon alfa
• Ribavirin -> nucleoside analogue prevents viral RNA synthesis
• Boceprevir -> protease inhibitor (Most effective against Hep C genotype )

Question 7

Tenofovir

Answer 7

• nucleotide analogue
• given sometimes with peg interferon alpha to treat hepatitis B
• also used in HIV
• as soon as you stop tenofovir the virus comes back

Question 8

What is the goal of hep C treatment today?

Answer 8

The goal of HCV treatment TODAY is to cure the virus

-> combination of drugs

Question 9

The specific drugs and the duration of HCV treatment depend on….. (6)

Answer 9

• HCV genotype (genetic structure of the virus)
• viral load
• past treatment experience
• degree of liver damage
• ability to tolerate the prescribed treatment
• need for liver transplant

Question 10

Summarise the HIV life cycle

Answer 10

1. Attachment & Entry
   - Viral membrane proteins interact with leukocyte membrane receptors
   - Viral capsid endocytosis
2. Replication & Integration
   - Within cytoplasm - reverse transciptase enzyme converts viral RNA -> DNA
   - DNA transported into nucleus & integrated into host DNA
3. Assembly & Release
   - Host cell’s ‘machinery’ utilised to produce viral RNA & essential proteins
   - Virus is assembled within cell -> mature virion is released

Question 11

HIV attachment and entry

Answer 11

• HIV Glycoprotein (GP)120 attaches to CD4 receptor
• GP120 also binds to either CCR5 or CXCR4
• GP41 penetrates host cell membrane & viral capsid enters

Question 12

Drugs that target HIV attachment and entry

Answer 12

• Enfuvirtide: Binds to HIV GP41 transmembrane glycoprotein

- Maraviroc: Blocks CCR5 chemokine receptor

Question 13

Enfuviritide

Answer 13

• used to treat HIV

- binds to GP41 transmembrane glycoprotein

Question 14

Maraviroc

Answer 14

• used to treat HIV

- blocks CCR5 chemokine receptor

Question 15

HIV replication

Answer 15

a) Reverse transcription: Viral single-stranded RNA -> double stranded DNA by reverse transcriptase
b) Integration: DNA integration
Viral integrase inserts viral DNA into host DNA

Question 16

Name HIV replication inhibitor types and how they work

Answer 16

• Nucleoside RT inhibitors
  Activated by 3 step phosphorylation process
  E.g. Zidovudine
• Nucleotide RT inhibitors
  Fewer phosphorylation steps required
  E.g. Tenofovir
• Non-nucleoside RT inhibitors
  No phosphorylation required
  Not incorporated into viral DNA
  E.g. Efavirenz

Question 17

Zidovudine

Answer 17

• nucleoside RT inhibitors
• activated by 3 step phosphorylation process
• also known az AZT
• when given for HIV the virus becomes resistant soon so it only works for a while and should be given as part of triple therapy

Question 18

How does Tenofovir work? Which conditions is it used for?

Answer 18

• used in Hep B and HIV
• RT inhibitor
• nucleotide analogue
• fewer phosphorylation steps are needed than for activation

Question 19

Efavirenz

Answer 19

• non nucleoside RT inhibitor
• no phosphorylation required
• not incorporated into viral DNA
• has many SE including nightmares, night sweats, insomnia, anxiety, depression.

Question 20

Which drugs are part of the triple therapy in HIV?

Answer 20

?

Question 21

How is HIV treated now?

Answer 21

Triple therapy

Question 22

HIV integrale inhibitor example

Answer 22

Raltegravir

Question 23

Raltegravir

Answer 23

• first of three licensed integrates inhibitors

Question 24

Assembly and release in HIV

Answer 24

• Gag precursor -> encodes all viral structural proteins
• HIV protease cleaves Gag precursor protein

Drugs: Protease inhibitors

Question 25

Name some protease inhibitors used for HIV

Answer 25

Saquinavir | Ritonavir

Question 26

Saquinavir

Answer 26

- 1st generation protease inhibitor | stops HIV protease from claeaving Gag chains (Gag precursor encodes all viral structural proteins

Question 27

Ritonavir

Answer 27

- low dose reduces PI metabolism - co-administered booster - now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors.

Question 28

Herpes simplex virus (Virology, tropism and treatment)

Answer 28

Virology - Double-stranded DNA - Surrounded by tegument & enclosed in a lipid bilayer Tropism - Herpes Simplex Virus (HSV)-1 -> cold-sores - HSV-2 -> genital herpes Treatment Nucleoside analogues -> Aciclovir

Question 29

Influenza

Answer 29

Virology - Multipartite single stranded RNA virus - Envelope protein neuraminidase -> release Tropism - Nose, throat & bronchi Treatment - Neuraminidase inhibitor -> Oseltamivir

Question 30

Acyclovir

Answer 30

Nucleoside analogue used to treat Herpes simplex

Question 31

Oseltamivir

Answer 31

= Neuraminidase inhibitor used to treat influenza

Question 32

Name some viral capsid proteins and drugs targeting them (3)

Answer 32

- HIV GP41 Enfuvirtide prevents HV fusion & entry - Macrophage CCR5 receptor Maraviroc inhibits CCR5 receptor - Influenza neuraminidase Oseltamivir inhibits influenza virus neuraminidase

Question 33

Name some nucleoside analogues that are used as antiviral treatment (3 diseases, 5 drugs)

Answer 33

HIV - Nucleoside (e.g. zidovudine) & nucleotide RT inhibitors bind to active site of enzyme - Efavirenz -> non-nucleoside binds to allosteric site on RT enzyme Hepatitis Hep B -> Tenofovir (RT inhibitor) Hep C -> Ribavirin (purine analogue) Herpes Simplex: Aciclovir -> nucleoside analogue

Question 34

Drugs targeting viral integrase

Answer 34

- raltegravir - used in HIV - inhibits the viral integrate enzyme

Question 35

Drugs targeting proteases

Answer 35

HIV - Saquinavir -> protease inhibitor - Ritonavir -> booster Hepatitis C - Boceprevir

Question 36

LO1: Distinguish between different types of virus and describe how they use the host cell to replicate (4)

Answer 36

- HIV - Retrovirus, leukocytes - Hepatitis - DNA & RNA viruses, hepatocytes - Herpes Simplex - DNA virus - Influenza - RNA virus

Question 37

LO2: Summarise the MoA of antiretroviral drugs

Answer 37

- Entry inhibitors - Enfuvirtide & Maraviroc - RT inhibitors - Nucleoside analogues (Zidovudine), Non-nucleoside analogues (Efavirenz) - Integrase inhibitors - Raltegravir - Protease inhibitors - Saquinavir

Question 38

LO3: Describe the actions of other antiviral drugs (not anti-retroviral?)

Answer 38

- Nucleotide analogues - Ribavirin, Aciclovir - Protease inhibitors - Boceprevir - Neuraminidase inhibitors - Oseltamivir