Targeting Pathogenic Organisms: Viruses

Question 1

do viruses have a genome

Answer 1

yes: either DNA or RNA

Question 2

problem with viruses like covid

Answer 2

mutation

Question 3

unique viral targets

Answer 3

structurally distinct polymerase
viral proteins

Question 4

3 diff ways viral infections manifest

Answer 4

-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.

Question 5

What are the 3 types of antiviral?

Answer 5

+Broad acting antivirals
+Direct acting antivirals (DAA)
+Immunomodulation (improves the immune response)

Question 6

most broad acting antivirals were first what?

Answer 6

anticancer agents

Question 7

MOA broad acting antivirals

Answer 7

prevent dna/rna synthesis.

Nucleoside/nucleotide analogues incorporate themselves into the DNA/RNA chain and cause chain termination.

Question 8

nucleoside vs nucleotide

Answer 8

Nucleoside: base and pentose. Nucleotide: base, pentose and phosphate.

Question 9

potency of broad acting

Answer 9

exhibit low potency but show some activity in a range of viruses.

Question 10

resistance mechanism of broad acting

Answer 10

RNA viruses become resistant to broad spectrum antivirals if used as monotherapy.

Question 11

what 2 scenarios are broad spectrum antivirals still prescribed for

Answer 11

i) emerging viral pathogens E.g., COVID-19.

ii) some DNA viruses for which there are not extensive DAAs available for.

Question 12

Why are nucleoside and nucleotide inhibitors not toxic to humans?

Answer 12

They are used by viral, but not human polymerases, in DNA replication.

Question 13

what are DAAs?

Answer 13

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)

Question 14

MOA nucleoside/nucleotide analogues

Answer 14

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.

Question 15

MOA Non-nucleotide/nucleoside inhibitors

Answer 15

• 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.

Question 16

MOA viral proteases

Answer 16

• 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

Question 17

MOA integrase inhibitors

Answer 17

• 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.

Question 18

disadvantages of DAA targeting DNA viruses

Answer 18

• Poor bioavailability so use by IV
• Nephrotoxicity in elderly patients or those with renal dysfunction

Question 19

main disadvantage of non-nucleoside/nucleotide inhibitors

Answer 19

Resistance can still occur

Question 20

disadvantages of DAA targeting viral proteases

Answer 20

• 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.

Question 21

SVR vs barrier to resistance

Answer 21

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’.

Question 22

importance of immunomodulation

Answer 22

• 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).

Question 23

enhancing immune response

Answer 23

-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

Question 24

dampening immune response

Answer 24

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.

Question 25

are there vaccines for viruses

Answer 25

yes. many.

Question 26

types of vaccines towards viruses

Answer 26

-Live, attenuated, reduced virulence but still live (chickenpox, MMR) = best type
-Subunit vaccine (HepB)
-Inactivated, whole virus vaccines (Flu)
-mRNA vaccines (SARS-CoV-2)

Question 27

PEP/PrEP

Answer 27

-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

Question 28

3 important factors for PEP/PrEP

Answer 28

time, cost, availability