16-11-22 – The Mechanism of Action of Anti-viral drugs Flashcards
Learning outcomes
- Describe viruses and their basic biology that makes treatment possible
- List the main classes of anti-viral and their mechanisms
- List the main indications for anti-viral treatment
- Demonstrate understanding of the particular challenges of antiviral treatment in normal clinical practice
What are viruses?
How do non-enveloped and enveloped viruses compare?
Describe the structure of enveloped and non-enveloped viruses (in picture)
- Viruses are sub-microscopic infectious agents (80-1400nm diameter)
- They are obligate intracellular parasites, meaning they are reliant on the host’s cells in order to function and replicate (use host cell machinery)
- Non-enveloped viruses tend to be stronger than enveloped viruses
- Enveloped viruses are not as easily transmitted, and they need the envelope to survive
What are the 5 ways we can classify viruses?
What is the formal way of classifying viruses?
- 5 ways we can classify viruses:
1) Route of transmission (e.g. arboviruses (norovirus))
2) The diseases they cause (e.g. viral haemorrhagic fevers)
3) Size / shape (e.g. filoviruses)
4) Appearance of the capsid (e.g. icosahedral vs. helical)
5) Presence or absence of a lipid envelope
- The formal way of classifying viruses is Baltimore classification system, which is based on the mechanism of mRNA production
What are the 4 different ways some viruses go through transcription?
- 4 different ways some viruses go through transcription:
1) Retroviruses
* Are ‘reverse transcribed’ to DNA via reverse transcriptase and integrated to the host genome
2) DNA viruses
* Require transcription to mRNA
3) Positive sense (+) RNA viruses
* Contain RNA in 5’-3’ orientation which can be directly used as mRNA for translation into proteins
* Can be replicated faster
4) Negative sense (-) RNA viruses
* Contain RNA in 3’-5’ orientation which requires conversion to 5’-3’ before translation into proteins
What are the 7 different classes of viruses based on nucleic acid?
What is an example of each class (in picture)?
How are most viruses treated?
What are 3 different mechanisms of action in anti-viral therapy?
What can they be used for?
- Most viruses are self-limiting, and will resolve on their own
- 3 different mechanisms of action in anti-viral therapy:
1) Virucides
* Can be used for viruses on the external surfaces e.g warts
* Detergents
* organic solvents
* UV light
* Cryotherapy
* Laser
* Podophyllin
2) Anti-viral drugs
* Ineffective vs. non-replicating / latent viruses
* Targets the stages in the viral life cycle of replicating viruses
3) Immunomodulators
* Replace deficient host response
* Enhance endogenous (internal) response
* They can reduce host response in order to reduce physical harm while the virus goes away by itself
What are stages in the viral life cycle targets for?
What are the 8 stages of the viral life cycle?
- Stages in the viral life cycle are all potential targets for anti-viral drugs
- 8 stages of the viral life cycle:
1) Attachment
2) Penetration
3) Disassembly
4) Transcription* - *(+)ssRNA viruses don’t need to be transcribed: can undergo direct translation in the host cell cytoplasm
5) Translation
6) Replication
7) Assembly
8) Release
What are 4 examples of targets for anti-viral drugs, the viruses, they’re used for, and the drugs used?
What are 4 examples of targets for anti-viral drugs, the viruses, they’re used for, and the drugs used?
What are analogue drugs? How can chemical/biological effects differ with analogue drugs?
What can nucleoside analogues be used for?
How is this done?
What viruses can this be used for?
When will it not work?
- An analogue drug is a drug that’s physical structure is related to that of another drug.
- Although they have similar physical properties, analogs can have very different chemical and biological properties.
- Nucleoside analogues can be used to prevent viral replication by interfering with nucleic acid replication, transcription and translation
- This is done by analogues compounds competing with essential nucleosides for binding sites in these processes
- This can be used for HSV (herpes) simplex virus DNA replication
- In this case, the nucleoside analogue aciclovir is used to as a competitive guanosine inhibitor to stop the process of DNA replication
- This will be used in cases of cold sores developing from HSV, otherwise it doesn’t work due to HSV being a latent virus
What are examples of drug analogues used for each of the 4 nucleosides?
What viruses are they used to treat?
What are examples of drug analogues used for each of the 4 nucleosides (in picture)?
What viruses are they used to treat?
What are 4 considerations of anti-viral therapy?
- 4 considerations of anti-viral therapy:
1) Effectiveness and aim of therapy
* Viral suppression or eradication?
* Does the medication improve clinical outcomes? E.g medication reducing a headache from 5 days to 3 days, is it necessary?
* Does every patient need it or are there ‘high risk’ groups?
2) Toxicity and side effects
3) Drug-drug interactions
4) Emergence of resistance
* Depends on the virus and the drug
* Possibly overcome by multi-drug therapy
How does anti-viral resistance arise?
What is selective pressure?
What are 5 things development of resistance is favoured by?
- Anti-viral drug resistance arises from mutations within the viral genome (viruses can make a lot of mistakes that cause mutations when replicating)
- The selective drug pressure will influence the level of resistant viral population
- Selective pressure is when a factor in the environment causes one type of organism to develop and grow in preference to another.
- With HIV drug resistance, the presence of a drug exerts selective pressure for resistance to develop
- 5 things development of resistance is favoured by:
1) High viral load
* The more virus particles replicating, the more mutations there will be
2) High intrinsic viral mutation rate (error prone, esp. RNA viruses)
3) Degree of selective drug pressure
* With HIV drug resistance, the presence of a drug exerts selective pressure for resistance to develop
4) ‘Resistance’ barrier of drug class / individual agent
* Will mutations in the virus allow it to overcome the effects of the drug used?
* A genetic barrier to resistance can be defined basically as the number of mutations required to confer resistance.
* For instance, NNRTIs have a low genetic barrier as a single mutation can cause resistance to most agents, whereas PIs have a high genetic barrier as multiple mutations are required.
5) Antiviral target that can mutate without affecting fitness
6 Examples & learning from clinical practice
- 6 Examples & learning from clinical practice:
1) HIV
2) Hepatitis C
3) Hepatitis B
4) Herpes viruses (e.g., Herpes Simplex Viruses, Cytomegalovirus)
5) Influenza
6) SARS CoV-2
What type of virus is HIV?
What does it contain?
What does this allow HIV to do with its genetic material?
What are CD4 cells?
How does HIV affect them?
What is another example of a human retrovirus?
What can some RNA retroviruses do to normal cells?
- HIV is a (+)ss RNA-RT retrovirus
- HIV contains Reverse Transcriptase (RT) - an RNA-dependent DNA polymerase, which makes a DNA copy of the viral RNA
- The DNA copy is integrated into the genome of the host cell (often CD4 cells)
- This provirus DNA is transcribed into both new genomic RNA and mRNA for translation into viral proteins using host cell machinery
- CD4 cells are a type of white blood cell
- CD4 cells killed by invading virus and host becomes dangerously immune-suppressed
- Another human retrovirus is Human T Lymphotropic Virus (HTLV)
- Some RNA retroviruses can transform normal cells into malignant cells
What are the 3 main routes of transmission of HIV?
How does deterioration link to loss of CD4 cells in HIV?
- 3 main routes of transmission of HIV:
1) Sexual
2) Parenteral (administered or occurring elsewhere in the body than the mouth and alimentary canal)
3) Vertical
- Deterioration link to loss of CD4 cells in HIV:
1) Early
* 10 weeks to 5 years
* CD4 around 800 to 500 (1000 cells per µl)
* Patient becomes auto-immune
2) Intermediate
* 5 years to 10 years
* CD4 around 500-200
* Patient can experience:
* Weight loss
* Fever
* Diarrhoea
* Herpes Zoster (shingles)
* Muco-cutaneous issues
* TB
* Sinusitis
* HSV
3) Advanced
* More than 10 years
* CDT <200
* Patient can experience:
* Oral candidiasis
* Hairy leukoplakia
* Cryptosporidiosis
* Pneumocystis
* Toxoplasmosis
* Cryptococcus
* CMV
* Kaposi
* NHL
* Dementia
Label the structures of the HIV virus and what each part is used for
Label the structures of the HIV virus and what each part is used for
How does HIV enter cells?
What are 2 different types of HIV entry inhibitors?
What is 1 example of each?
- Entry of HIV into a new cell is mediated by the Env glycoprotein spike (a trimer of gp120 and gp41) Entry requires the receptor
- CD4 plus one of two co-receptors, CCR5 or CXCR4
- 2 different types of HIV entry inhibitors:
1) Fusion inhibitor
* Enfuvirtide - T20
* Synthetic peptide
* Subcutaneous administration
* Side effects – rarely used as first line
2) CCR5 antagonist
* Maraviroc
* Binds to CCR5
What are 2 different classes of reverse transcriptase inhibitors?
- 2 different classes of reverse transcriptase inhibitors:
1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
* Nucleoside analogues which compete with reverse transcription preventing viral pro-DNA synthesis
* Also affect host cell DNA synthesis causing toxicity
2) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
* Drugs which bind directly to RT causing conformational change which stops the enzyme from working
What are the 2 critical reactions that HIV integrase mediates?
What are 4 examples of integrase inhibitors?
- 2 critical reactions that HIV integrase mediates:
1) 3’end processing of the double-stranded viral DNA ends
2) Strand transfer which joins the viral DNA to the host chromosomal DNA forming a provirus
- 4 examples of integrase inhibitors:
1) Raltegravir
2) Dolutegravir
3) Elvitegravir
4) Bictegravir
How many drugs are typically given in antiretroviral therapy (ART)?
What are 2 reasons why is life-long drug therapy difficult to manage?
What are 2 ways around this?
What was the previous approach to ART?
What is the new approach to ART?
What improvements does the new approach allow?
When is HIV considered untransmittable?
What are the long-term adverse effects from ART (in picture):
* NRTI (2 agents)
* NNRTI (1 agent)
* PI (3 agents)
* INSTI (1 agent)
- In antiretroviral therapy (ART), typically 3 drugs are given, often 2 NRTIs and an additional drug from another class (NNRTI, PI or Integrase Inhibitor)
- Life-long drug therapy is difficult to manage, as it can make patient adherence very difficult
- It also creates a higher risk of gradual acquisition of resistant viral mutations that will eventually stop treatment from working
- 2 ways around this are having greater adherence, or combination therapy, so we use a combination of 3 medications at a time
- Previously, the approach to ART was to defer ART until low CD4 count
- Now, early ART initiation improves long-term outcomes:
1) Reduction in sexual and vertical transmission of HIV
2) Restore and preserve immunological function
- HIV is considered untransmittable when it is undetectable
What family of virus is Hepatitis C part of?
What type of virus is it?
How is it transmitted?
What 3 things does Hepatitis C cause?
What was the original approach for Hepatitis C treatment?
Why were these not the best approach?
What are new treatments like now?
What is an example of a drug used in treatment now?
What is the aim of hepatitis C treatment now?
How is treatment for Hepatitis C classified?
- Hepatitis C is part of the Flaviviridae family
- Hepatitis C is a (+) ss RNA virus
- Primarily transmitted through parenteral route, sexual transmission also recognised
- 3 things Hepatitis C causes:
1) Acute and chronic hepatitis
2) Cirrhosis
3) Hepatocellular carcinoma
- The original approach for Hepatitis C treatment was was pegIFN-α & ribavirin for up to a year (anti-inflammatory therapy)
- These treatments were toxic and poorly efficacious
- There are many effective treatments now that are short and all oral e.g elbasvir
- The aim for Hepatitis C treatment now is sustained virological response – we cant find hepatitis in the body and we presume it wont come back, but we need to still monitor
- Treatment for Hepatitis C is classified by viral genotype and severity of liver disease
What family of viruses is Hepatitis B virus (HBV)
part of?
What type of virus is Hepatitis B?
What is its structure like?
What 3 things does Hepatitis B cause?
What is there a greater chance of with Hepatitis B?
How does Hepatitis B virus replicate?
- Hepatitis B virus (HBV) is part of the hepadnavirus family
- Hepatitis B is a partial dsDNA virus
- Hepatitis B is an enveloped virus and has its genome maintained in a circular conformation
- 3 things Hepatitis B causes:
1) Acute and chronic hepatitis
2) Cirrhosis
3) Hepatocellular carcinoma
- There is a higher chance of getting a more serious illness
- Main long term health consequences are driven by chronic rather than acute infection
- Replication occurs via RNA intermediate (template for HBV polymerase)
What family of viruses is influenza part of?
What type of virus is influenza?
What are the 3 different types of influenza?
When does influenza appear during the year?
What can influenza cause?
What groups are at higher risk of influenza?
Who is offered medication?
What is NA and HA on influenza viruses?
What are they essential for?
Where are they found?
- Influenza is part of the Orthomyxoviridae family
- Influenza is an Enveloped (-) ssRNA viruses
- The 3 different types of influenza are A, B, C
- Influenza appears as Seasonal epidemics (normally winter) and sporadic pandemics with variable severity
- Influenza is variable in severity and can cause anything from mild coryza (infection) to life threatening pneumonia
- Elderly & immune-compromised at highest risk
- Not everyone will be offered medications, but higher risk individuals will be
- HA is Hemagluttinin, and it is essential for host cell centre
- NA is Neuraminidase, and it is essential for virion release (virus release from host cell after replication)
- Both of these are found on the outer surface of the influenza virus
What does NA do?
What do NA inhibitors do?
What are 2 examples of Neuraminidase (NA) inhibitors?
- NA (Neuraminidase) cleaves a sialic acid receptor on host cell enabling viral release
- NA inhibitors competitively bind the NA binding site, preventing viral release
- 2 examples of NA inhibitors:
1) Oseltamivir - oral
2) Zanamivir – inhalational
What are 2 other examples of anti-influenza drugs?
- 2 other examples of anti-influenza drugs:
1) Amantadine/rimantadine
* Not used: high-level resistance
* Block M2 ion channel necessary for:
* Fusion of viral membrane and endosome membrane
* Late stage of assembly and release of new virions
2) Baloxavir
* Not currently used in UK
* Viral polymerase complex inhibitor
What type of virus is SARS-CoV-2?
What 4 structural proteins does SARS-CoV-2 have?
What does SARS-CoV-2 cause?
What kind of support is key in severe Covid-19?
What are 3 different parts in the drug treatment of Covid-19?
- SARS-CoV-2 is a (+) ssRNA virus
- 4 structural proteins that SARS-CoV-2 has (SEMN):
1) Spike (S) protein facilitates host cell entry via ACE2 receptor
2) Envelope (E) proteins
3) Membrane (M) proteins
4) Nucleocapsid (N) protein contains viral genome
- SARS-CoV-2 virus causes Covid-19
- In severe cases of Covid-19, Oxygen & ventilatory support is key
- 3 different parts in the drug treatment of Covid-19:
1) Anti-virals
* Prevents virus from multiplying
* Remdesivir – adenosine analogue
* Molnupiravir – promotes errors in viral replication
2) Anti-inflammatories
* Calms immune response
* Dexamethasone
* Toculizumab
3) Antibody treatments
* Binds to antigens on virus and kill the virus
* Can go from being very effective to not working at all
