Targeting Pathogenic Organisms: Viruses Flashcards
do viruses have a genome
yes: either DNA or RNA
problem with viruses like covid
mutation
unique viral targets
structurally distinct polymerase
viral proteins
3 diff ways viral infections manifest
-Acute = are of relatively short duration with rapid recovery.
-Chronic = characterized by the continued presence of infectious virus following the primary infection and may include chronic or recurrent disease.
-Latent = characterized by the lack of demonstrable infectious virus between episodes of recurrent disease.
Increases in treatment difficulty with latent being most difficult to treat due to reactivation e.g., chickenpox & shingles, HSV.
What are the 3 types of antiviral?
+Broad acting antivirals
+Direct acting antivirals (DAA)
+Immunomodulation (improves the immune response)
most broad acting antivirals were first what?
anticancer agents
MOA broad acting antivirals
prevent dna/rna synthesis.
Nucleoside/nucleotide analogues incorporate themselves into the DNA/RNA chain and cause chain termination.
nucleoside vs nucleotide
Nucleoside: base and pentose. Nucleotide: base, pentose and phosphate.
potency of broad acting
exhibit low potency but show some activity in a range of viruses.
resistance mechanism of broad acting
RNA viruses become resistant to broad spectrum antivirals if used as monotherapy.
what 2 scenarios are broad spectrum antivirals still prescribed for
i) emerging viral pathogens E.g., COVID-19.
ii) some DNA viruses for which there are not extensive DAAs available for.
Why are nucleoside and nucleotide inhibitors not toxic to humans?
They are used by viral, but not human polymerases, in DNA replication.
what are DAAs?
specific to a unique bacterial process
a) Nucleoside/nucleotide analogues
b) Non-nucleotide/nucleoside inhibitors
c) Viral proteases (HIV, SARS-CoV-2, HepC)
d) Integrase inhibitors (HIV, HepB)
MOA nucleoside/nucleotide analogues
used for RNA viruses and DNA viruses:
Incorporate themselves leading to chain termination.
RNA viruses:
Highly effective but should not be used as a monotherapy.
DNA viruses:
- Treating DNA viruses can be more challenging in many ways.
- Acyclic guanosine nucleoside analogues have good antiviral activity against HSV, HPV, CMV and VSZ.
MOA Non-nucleotide/nucleoside inhibitors
- These work by directly interfering with the viral polymerase
- Allosteric hinderance and blocking channels in this enzyme
- Usually used in combination with analogue inhibitors so not alone as monotherapy.
MOA viral proteases
- Many viruses produce a functional viral protease → cleaves viral polypeptide into functional protein subunits → produces mature infectious virions.
- DAAs can be used against these unique viral proteases
- Complement analogue and non-analogue HIV therapy, but other great drugs also made
MOA integrase inhibitors
- A few viruses integrate their genomes into the DNA of the host e.g., HIV and Hepatitis B virus
- Integrase inhibitors work to prevent integration into the host genome
- BUT do not revert integration that has already taken place.
- Prescribed in more complex HIV cases where other DAA resistance, SE and interference with other medications are an issue.
disadvantages of DAA targeting DNA viruses
- Poor bioavailability so use by IV
- Nephrotoxicity in elderly patients or those with renal dysfunction
main disadvantage of non-nucleoside/nucleotide inhibitors
Resistance can still occur
disadvantages of DAA targeting viral proteases
- GI disturbances (Diarrhoea)
- metabolised quickly via cytochrome P450 → decreases their activity. So, need to be given with Ritonavir which works itself as a viral protease inhibitor but also inhibits metabolism via the CYP3A4 enzyme → improving bioavailability.
SVR vs barrier to resistance
SVR = aviraemia after end of treatment
Barrier to resistance = ‘whole number of mutations in a virus drug targets required to confer a clinically meaningful loss of susceptibility to a drug’.
importance of immunomodulation
- Many viruses induce a potent pro-inflammatory immune response. It is this response that can be so damaging (flu, COVID-19).
- In other examples, the immune response is weak and does not suppress or clear viral infection (e.g., Hep C or Hep B).
enhancing immune response
-Interferons: basic type of cytokine linked to the innate antiviral immune response. Stimulate both the innate and later acquired immune response to combat a viral pathogen. Regular treatment for chronic infections. BUT, many side effects and so poor compliance.
-Synthetic compounds like Imiquimod stimulate macrophage involvement – HPV and other conditions (skin cancer).
-Monoclonal or serum-derived antibodies that target antiviral proteins also used to boost viral clearance
dampening immune response
Tocilizumab = monoclonal antibody. Binds and blocks IL-6 receptors. IL-6 is a pro-inflammatory cytokine. Initially used for pro-inflammatory autoimmune diseases like rheumatoid arthritis.
are there vaccines for viruses
yes. many.
types of vaccines towards viruses
-Live, attenuated, reduced virulence but still live (chickenpox, MMR) = best type
-Subunit vaccine (HepB)
-Inactivated, whole virus vaccines (Flu)
-mRNA vaccines (SARS-CoV-2)
PEP/PrEP
-Direct acting antivirals e.g. Antiretroviral therapy (HIV), remdesivir (Ebola, SARS-CoV-2), ribavirin (broad spectrum)
-Convalescent serum from recovered patient (high titre immunoglobulins esp. IgG)
Rabies virus/animal bites (as well as rabies vaccine)
SARS-CoV-2 in clinically vulnerable individuals
Ebola virus
Chickenpox virus in clinically vulnerable individuals
3 important factors for PEP/PrEP
time, cost, availability
