Antivirals (13.03.2020) Flashcards
Structure of a virus (4 main components)
- 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)
Distinguish between different types of virus and describe how they use the host cell to replicate
- HIV - Retrovirus, leukocytes
- Hepatitis - DNA & RNA viruses, hepatocytes
- Herpes Simplex - DNA virus
- Influenza - RNA virus
Summarise viral hepatitis
- Tropism: Liver hepatocytes
- Hepatitis (Hep) B & C: Only chronic infection requires treatment
Summarise the treatment for hepatitis B
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)
Summarise the treatment for hepatitis C
- Ribavirin & Peginterferon alfa
Ribavirin -> nucleoside analogue prevents viral RNA synthesis - Boceprevir -> protease inhibitor
Most effective against Hep C genotype 1
Describe the pharmacological treatment of different types of hepatitis:
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 )
Tenofovir
- 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
What is the goal of hep C treatment today?
The goal of HCV treatment TODAY is to cure the virus
-> combination of drugs
The specific drugs and the duration of HCV treatment depend on….. (6)
- 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
Summarise the HIV life cycle
- Attachment & Entry
- Viral membrane proteins interact with leukocyte membrane receptors
- Viral capsid endocytosis - Replication & Integration
- Within cytoplasm - reverse transciptase enzyme converts viral RNA -> DNA
- DNA transported into nucleus & integrated into host DNA - Assembly & Release
- Host cell’s ‘machinery’ utilised to produce viral RNA & essential proteins
- Virus is assembled within cell -> mature virion is released
HIV attachment and entry
- HIV Glycoprotein (GP)120 attaches to CD4 receptor
- GP120 also binds to either CCR5 or CXCR4
- GP41 penetrates host cell membrane & viral capsid enters
Drugs that target HIV attachment and entry
- Enfuvirtide: Binds to HIV GP41 transmembrane glycoprotein
- Maraviroc: Blocks CCR5 chemokine receptor
Enfuviritide
- used to treat HIV
- binds to GP41 transmembrane glycoprotein
Maraviroc
- used to treat HIV
- blocks CCR5 chemokine receptor
HIV replication
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
Name HIV replication inhibitor types and how they work
- 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
Zidovudine
- 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
How does Tenofovir work? Which conditions is it used for?
- used in Hep B and HIV
- RT inhibitor
- nucleotide analogue
- fewer phosphorylation steps are needed than for activation
Efavirenz
- non nucleoside RT inhibitor
- no phosphorylation required
- not incorporated into viral DNA
- has many SE including nightmares, night sweats, insomnia, anxiety, depression.
Which drugs are part of the triple therapy in HIV?
?
How is HIV treated now?
Triple therapy
HIV integrale inhibitor example
Raltegravir
Raltegravir
- first of three licensed integrates inhibitors
Assembly and release in HIV
- Gag precursor -> encodes all viral structural proteins
- HIV protease cleaves Gag precursor protein
Drugs: Protease inhibitors
Name some protease inhibitors used for HIV
Saquinavir
Ritonavir
Saquinavir
- 1st generation protease inhibitor
stops HIV protease from claeaving Gag chains (Gag precursor encodes all viral structural proteins
Ritonavir
- 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.
Herpes simplex virus (Virology, tropism and treatment)
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
Influenza
Virology
- Multipartite single stranded RNA virus
- Envelope protein neuraminidase -> release
Tropism
- Nose, throat & bronchi
Treatment
- Neuraminidase inhibitor -> Oseltamivir
Acyclovir
Nucleoside analogue used to treat Herpes simplex
Oseltamivir
= Neuraminidase inhibitor
used to treat influenza
Name some viral capsid proteins and drugs targeting them (3)
- HIV GP41
Enfuvirtide prevents HV fusion & entry - Macrophage CCR5 receptor
Maraviroc inhibits CCR5 receptor - Influenza neuraminidase
Oseltamivir inhibits influenza virus neuraminidase
Name some nucleoside analogues that are used as antiviral treatment (3 diseases, 5 drugs)
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
Drugs targeting viral integrase
- raltegravir
- used in HIV
- inhibits the viral integrate enzyme
Drugs targeting proteases
HIV
- Saquinavir -> protease inhibitor
- Ritonavir -> booster
Hepatitis C
- Boceprevir
LO1: Distinguish between different types of virus and describe how they use the host cell to replicate (4)
- HIV - Retrovirus, leukocytes
- Hepatitis - DNA & RNA viruses, hepatocytes
- Herpes Simplex - DNA virus
- Influenza - RNA virus
LO2: Summarise the MoA of antiretroviral drugs
- Entry inhibitors - Enfuvirtide & Maraviroc
- RT inhibitors - Nucleoside analogues (Zidovudine), Non-nucleoside analogues (Efavirenz)
- Integrase inhibitors - Raltegravir
- Protease inhibitors - Saquinavir
LO3: Describe the actions of other antiviral drugs (not anti-retroviral?)
- Nucleotide analogues - Ribavirin, Aciclovir
- Protease inhibitors - Boceprevir
- Neuraminidase inhibitors - Oseltamivir
