Mechanism of Antivirals Flashcards
List some different types of antimicrobials.
- Antibiotics
- Antivirals
- Anti-fungals
- Anti-protosoals
- Anti-helminths
Why do we need antivirals?
There are many different types of viral disease with detrimental effects:
- quick killers e.g. influenza; EBOLA; MERS; SARS
- slow, progressive chronic disease leading to things like cancer (hepatitis B [350,000,000 carriers],
hepatitis C [200,000,000 carriers],
human papilloma viruses [cervical cancer, second commonest cancer in women]) - highly infectious (human immunodeficiency virus (HIV) [40 million infected])
- acute imflammatory diseases e.g. herpes
List some uses of antivirals.
- treatment of acute infection (influenza; chickenpox; herpes infections - [with aciclovir])
- treatment/control of chronic infection (HCV, HBV, HIV [numerous different agents])
- post-exposure prophylaxis and preventing infection (HIV [PEP])
- pre-exposure prophylaxis (HIV [PrEP])
- prophylaxis for reactivated infection (e.g. in transplantation when you are immunocompromised; CMV [ganciclovir, foscarnet])
List some principles of selective toxicity of antivirals as therapeutic agents.
It is based on the differences in structure and metabolic pathways between host and pathogen.
It harms the microorganisms, not the host.
We want the target to be in the microbe, not the host (if possible).
Selective toxicity is difficult for viruses (intracellular), fungi and parasites because they’re intracellular organisms.
We need to understand that there is variation between microbes, strains within the same species.
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 – this obligates intracellular parasites
- viruses take over the host cell replicative machinery, so it is hard not to harm the cell as well
- viruses have high a mutation rate - this creates quasispecies (a large number of mutants of the same isolate of virus)
- antivirals 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 so it’s harder to remove them as they are not presenting themselves e.g. herpes, HPV
- some viruses are able to integrate their genetic material into host cells e.g. HIV
Briefly, recap the virus life cycle.
Essentially, the virus comes in and attaches to the membrane, and then get internalized, either by the mechanism of endocytosis or by membrane fusion. This means there are processes that associate the virus with the cell membrane, so this is a potential site of drug activity.
Once the virus is inside, it has to un-coat and release its genome. That genome has to replicate itself and also has to make mRNA, and goes to the ribosomes of the cell, where it starts to make viral proteins.
The virus will then reassemble, either by budding through the membrane, or they assemble completely inside the cell and get out via lysis of the cell.
What are some considerations in developing safe antivirals?
Can certain stages of infection be targeted?
Cellular receptors may have other important functions.
Viral enzymes may be very similar to host enzymes.
Blocking the cellular enzyme may kill the cell.
What are some modes of action of selected antivirals?
- preventing virus adsorption onto host
- preventing penetration
- preventing viral nucleic acid replication (nucleoside analogues)
- preventing maturation of virus
- preventing virus release
List some examples of antivirals and how they work.
Amantadine blocks the process of uncoating. It’s an effective anti-flu drug, but it has a lot of toxicity associated with it.
Acyclovir, Ganciclovir and Ribavirin inhibit nucleic acid polymerisation, by targeting either reverse transcriptases or DNA polymerases.
Ribavirin blocks the access and is an analogue of GTP, and compromises genome replication.
Interferons inhibit the synthesis of RNA or the replication of the genome.
Protease inhibitors block the process of particle maturation and assembly of protein particles that are generated from the genome of the virus.
Zanamivir blocks the release of the virus from the cell.
What are some examples of selective toxicity viral targets?
The discovery of virally encoded enzymes sufficiently different from their human counterparts means that they can act as selective targets with minimal effect on the host enzymes or processes.
Examples are:
- thymidine kinases (used for treating herpes-like infections) of HSV/VZV/CMV
- proteases of HIV
- reverse transcriptases of HIV
- DNA polymerases
- neuraminidases of influenza virus
List the drugs that treat herpes viruses.
Aciclovir:
- for HSV, VZV treatment/ prophylaxis of CMV
- CMV/EBV prophylaxis
GANCICLOVIR:
- for CMV
FOSCARNET:
- for CMV
CIDOFIR:
- for CMV
Describe the mechanism of action of Aciclovir.
Aciclovir is an analogue of GTP. It is missing it’s sugar phosphate ring, so it would be called a ‘chain terminator’. It will be inserted into the DNA and prevents it from polymerising.
First, it has to be activated.
It is first phosphorylated by a viral thymidine kinase (TK), then it gets di- and tri-phosphorylated by cellular kinases. It is only active in the tri-phosphate form.
It then becomes a competitive inhibitor of the viral DNA Polymerase. It will compete for standard GTP, and will stop the viral Polymerase from synthesising the viral genome.
What two principles give Aciclovir selective toxicity?
- It is selectively activated inside cells that are infected; other cells do have their own thymidine kinase, but it has very poor activity against the acyclovir molecule.
- It is also selectively inhibits only viral DNA Polymerase, as it is 30 times more effective against them.
Why is Aciclovir so effective and safe?
HSV thymidine kinase (TK) has 100x the affinity for Aciclovir 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) thus, it will accumulate in cells that are infected.
It is a DNA chain terminator.
What is Aciclovir used to treat?
HERPES SIMPLEX:
- treatment of encephalitis
- treatment of genital infection
- suppressive therapy for recurrent genital herpes
VARICELLA ZOSTER VIRUS:
- treatment of chickenpox
- treatment of shingles
- prophylaxis of chickenpox
CMV/EBV
- prophylaxis only