Mechanism of Antivirals Flashcards
Why do we need antivirals?
- Needed for quick killing infections- flu, Ebola, MERS, SARS.
- Needed for slow, progressive chronic disease, leading to cancer- hepatitis B/C and hpv.
- For HIV to prevent AIDS.
- For acute inflammatory viruses- herpes.
What are the 5 uses of antivirals?
- Treatment of acute infection
a. Influenza; Chickenpox; herpes infections -(aciclovir) - Treatment of chronic infection:
a. HCV, HBV, HIV (numerous different agents) - Post-exposure prophylaxis and preventing infection:
a. HIV (PEP) - Pre-exposure prophylaxis:
a. HIV (PrEP) - Prophylaxis for reactivated infection: e.g. in transplantation
a. CMV (ganciclovir, foscarnet)
b. To prevent viruses being reactivated
What does selective toxicity mean?
- Selective Toxicity - when a drug has an effect against one component but not another
- Due to the differences in structure and metabolic pathways between host and pathogen
- Harm microorganisms, not the host
- Target in microbe, not host (if possible)
- Difficult for viruses (intracellular), fungi and parasites
- Variation between microbes
- It has to have a very minimal on the host
- The target should be specific in the antigen but this is difficult as viruses require the host cell
Why is it so difficult to develop effective, non-toxic anti-viral drugs ?
- Viruses enter cells using cellular receptors which may have other functions
- Viruses must replicate inside cells – obligate intracellular parasites
- Viruses take over the host cell replicative machinery
- Virsues have high mutation rate - quasispecies
- Anti-virals must be selective in their toxicity
- i.e. exert their action only on infected cells
- Some viruses are able to remain in a latent state e.g. herpes, HPV
- Some viruses are able to integrate their genetic material into host cells. Therefore it is impossible to remove this integrated virus e.g. HIV
- If you block a receptor, it could have some toxic effects.
- Viruses can escape anti-viral drugs as they can have lots of mutations
What should we consider when developing antivirals?
- Can stages of infection be targeted?
- Cellular receptor may have other important function
- Viral enzymes may be very similar to host
- Blocking cellular enzyme may kill cell
Describe the life cycle of a virus
- Virus attaches to a membrane and then goes in via endocytosis or fusion
- It has to uncoat and release its genome
- It also has to make mRNA which goes on to the ribosomes in the cell where is starts to make viral proteins.
- The virus will then reassemble and can escape through cell lysis.
Describe the various modes of action of antivirals
- Preventing virus adsorption onto host cell
- Preventing penetration
- Preventing viral nucleic acid replication (nucleoside analogues)
- Preventing maturation of virus
- Preventing virus release
What are the 4 families of herpes virus and what can they be treated with?
Acyclovir- IV/oral/topical for HSV, VZV treatment/prophylaxis.
Ganciclovir- IV/oral for CMV/EBV prophylaxis
Foscarnet- IV/local application for CMV
Cidofovir- IV for CM
How does aciclovir work?
• Aciclovir is activated to active drug • Substantially more in infected cells • Requires 2 viral enzymes o Selectively activate ACV o Selectively inhibited • Accounts for low toxicity
- It is an analogue of GTP
- It doesn’t have a 3’ hydroxyl
- It will insert in the DNA and prevent it from polymerising
- It needs to be activated first
- It is phosphorylated first by a viral thymidine kinase
- It then remains stable and gets di,tri, phosphorylated by cellular kinases
- It is only active when it is tri phos…
- It is now an inhibitor for viral DNA polymerase
- It will compete from GTP and will stop the virus from making the viral genome
- It will only be phosphaylated in the presence of a virus as it needs a viral thymidine kinase
- GTP analogue acts on viral thymidine kinase.
- Activated to activated drug.
- Competitive inhibitor to HSV DNA pol.
- Requires 2 viral enzymes- selectively activated by HSV TK and selectively inhibited.
- Low toxicity as found substantially more in active form in cells with these enzymes- i.e. infected cells.
- HSV (herpes) thymidine kinase (TK) has 100x more affinity to ACV than cellular phosphokinases.
- Acyclovir triphosphate has 30x more affinity for HSV DNA pol compared to cellular DNA pol.
- Also, highly polar so difficulty leaving and entering cells but easily taken in before phosphorylation.
- Also, there is a DNA chain terminator.
Why is aciclovir so effective and safe?
- HSV thymidine kinase (TK) has 100x the affinity for ACV compared with cellular phosphokinases
- Aciclovir triphosphate has 30x the affinity for HSV DNA polymerase compared with cellular DNA polymerase
- Aciclovir triphosphate is a highly polar compound - difficult to leave or enter cells (but aciclovir is easily taken into cells prior to phosphorylation)
- DNA chain terminator
How does Ganciclovir work?
How is it activated?
What does it treat and what does it target?
- Active for CMV (cytomegalovirus). Reactivated infection or prophylaxis in organ transplant recipients.
- For congenital infection in newborns and retinitis in immunosuppressed.
- Structurally similar to acyclovir.
- CMV does not encode TK but has UL97 kinase.
- Inhibits CMV DNA polymerase.
How does FOSCARNET work?
What does it do?
What infection does it target?
• Selectively inhibits viral DNA/RNA polymerases and RTs
• No reactivation required
• Binds pyrophosphate binding site – a structural mimic
• Used for CMV infection in the immunocompromised
o e.g. pneumonia in solid organ and bone marrow transplants.
• May be used because of ganciclovir resistance (TK mutants)
How does CIDOFOVIR work?
- Chain terminator - targets DNA polymerase
- Competes with dCTP
- Monophosphate nucleotide analog
- Prodrug – phosphorylated by cellular kinases to di-phosphate
- drug active against CMV; but MUCH MORE nephrotoxic
- Treatment of retinitis in HIV disease
What are the 2 main mechanisms for resistance to anti-virals in Herpes Virus
• Two main mechanisms
- Thymidine Kinase mutants
If occurs in TK, drugs not needing phosphorylation are still effective (e.g. foscarnet, cidofovir) - DNA polymerase mutants
If occurs in DNA polymerase, all drugs rendered less effective
VERY RARE in immune competent patients (low viral load)
What are the types of HIV drugs?
Anti-reverse transcriptase inhibitors- nukes (nucleoside/nucleotide RT inhibitors- synthetic nucleoside thymidine analogue converted to di-nucleotide and then blocks RT by competing for substrate- dTTP- and incorporation into DNA by causing chain termination) and non-nukes (non-nucleotide RT inhibitors- allosteric. Non-competitive inhibitor of HIV-1 RT).
Protease inhibitors- multiple types
Integrase inhibitors – POL gene (protease, reverse transcriptase and integrase (IN) with the 3´end encoding for IN (polynucleotidyl transferase)).
Fusion inhibitors – gp120/41 - biomimetic lipopeptide.
Treatment - HAART- Combination of drugs to avoid resistance.
