Mechanism of Antivirals Flashcards
Explain 3 reasons why even though we have vaccines, we need antivirals
- There are poorly effective or no vaccines for some viruses important to human health
- Not everyone can be administered a vaccine even if that vaccine is effective
- Immune response to vaccine administration can take time (and several sequential administrations)
What type of infections might we need to use antivirals for?
- acute infections (aka quick killers) like influenza, ebola, MERS and SARS
- viruses that we do not have a vaccine for (like HIV - long term) and chronic infections
- viruses that cause acute inflammatory disease like herpes
What is prophylaxis?
Treatment given or action taken to prevent disease
When talking about HIV antivirals what is meant by PEP and PrEP?
- Post-exposure prophylaxis and preventing infection: HIV (PEP)
- Pre-exposure prophylaxis: HIV (PrEP)
Name some broad different modes of action of antivirals
- Preventing virus absorption into host cell
- Preventing penetration
- Preventing viral nucleic acid replication (nucleoside analogues)
- Preventing maturation of virus
- Preventing virus release
Explain why developing antiviral drugs that are non-toxic and effective is so hard
- Viruses use cellular proteins which may have other functions
- Viruses must replicate inside cells - obligate intracellular parasites
- Viruses take over the host cell replicative machinery
- Viruses 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
- e.g. HIV
What viruses does Aciclovir target?
Herpes virus family including:
- Herpes simplex (HSV)
- Varicella Zoster Virus (VZV)
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
Explain why Aciclovir only works in virus infected cells
This is as it starts as an inactive form and is converted to the active form by 2 viral enzymes
The viral enzyme {?} activates Aciclovir
The viral enzyme thymidine kinase (TK) activates Aciclovir
Explain what happens to Aciclovir to activate it
It is phosphorylated by a viral enzyme thymidine kinase (TK)
Explain how Aciclovir produces its antiviral effect
Aciclovir, when phosphorylated (by a viral enzyme?), looks like a DNA base so the viral DNA pol incorporates the active Aciclovir into the DNA
- Aciclovir is a DNA chain terminator
- Aciclovir has 30x the affinity for HSV DNA polymerase compared to cellular DNA polymerase
{?} has {?} the affinity for Aciclovir (ACV) compared with cellular phosphokinases
HSV thymidine kinase (TK) has 100 x the affinity for Aciclovir (ACV) compared with cellular phosphokinases
What viruses does Ganciclovir treat?
CMV (cytomegalovirus)
What type of virus is CMV (cytomegalovirus)?
Herpes
- Herpes virus 4
How does Ganciclovir work?
Is basically the same as Aciclovir but just uses a different enzyme that is specific to CMV (so is converted to an active form by a viral enzyme and then will competitively inhibit viral DNA pol?)
Which viral enzyme converts ganciclovir to its active form?
CMV phosphotransferase (UL97 kinase)
Name 2 anti-herpes drugs that are not aciclovir or ganciclovir
- Foscarnet
- Cidofovir
Name the 2 main mechanisms that viruses can become resistant to aciclovir
As there are 2 enzymes involved in the pathway, if there are mutations to these 2 specific enzymes then aciclovir can not work
Why is resitance to antivirals in herpes virus very rare?
As (in immune competent patients) there is a very low viral load
If a mutation occuurs in {?} in a herpes virus drugs not needing phsophorylation are still effective
If a mutation occuurs in Thymidine Kinase in a herpes virus drugs not needing phsophorylation are still effective
If a mutation in a herpes virus occurs in {?} all drugs are rendered less effective
If a mutation in a herpes virus occurs in viral DNA polymerase all drugs are rendered less effective
What virus does HAART target?
HIV
What type of genetic material is in HIV?
ss + RNA, 2 strands
Is HIV enveloped?
yes
What is gp120 on HIV?
The envelope protein, also uses the transmembrane protein gp41
- “ a glycoprotein protruding from the outer surface of the HIV virion that has a molecular weight of 120 and must bind to a CD4 receptor on a T cell bearing such receptors before infection of the cell can occur”
Explain what Gag (group specific antigen) is
Gag is the major structural protein of HIV and all retroviruses
Describe the structure of HIV
Name 4 types of anti-HIV drugs
- Anti-reverse transcriptase inhibitors
- Protease inhbitors
- Integrase inhibitors
- Fusion inhibitors
Why is it very common for HIV to produce anti-viral resitant HIV mutants?
Because it produces a large amount of mutations in its replication (reverse transcriptase lacks proof reading capacity?)
What is HAART and why do we do it?
Since HIV very often produces antiviral resistant mutants, we use a combination of different types of antiviral HIV drugs (4 types)
- this therapy is called HAART = highly active anti retroviral therapy
What is the most common type (class) of anti-HIV antiviral and name one
Nucleoside reverse transcriptase inhibitors (NRTI)
- AZT
Nucleoside reverse transcriptase inhibitors are one type of drug used in the treatment of HIV, explain how these work
They are structurally similar to DNA bases so reverse transcriptase incorporates them but they cause chain termination
In the treatment of HIV we can use non-nucleoside reverse transcriptase inhibitors, explain how these work
These do the same thing as nucleoside RT inhibitors but do not look like nucleotides
- non competitive inhibition of reverser transcriptase
- can be used in combination with NRTIs
What is meant by a viral swarm in HIV?
Due to the high mutation rate and high viral load, HIV can cause a large number of multiple different HIV viruses
- quasispecies
Why does HIV have a high mutation rate?
Reverse transcriptase lacks a proof reading capacity
What genetic material is in influenza?
single stranded (ss) RNA
What type of virus do we treat with Amantidine?
Influenza
How does Amantidine work?
- Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin
- Now rarely used
Zanamivir and Oseltamivir (Tamiflu) are used for treatment of flu, how do they work?
- Inhibits virus release from infected cells via inhibition of neuraminidase
- Oseltamivir-oral
- Zanamivir- inhaled or IV - less likely for resistance to develop
Explain how zanamivir and oseltamivir work
Stop the virus (flu) from leaving the cell as an interaction is needed by neuraminidise with the cell surface - they block this interaction
How is hepatitis C (HCV) transmitted?
- Unprotected sex
- Blood and body fluid exposure
- IV drug use
What type of virus (genetic material) is HCV (hepatitis C)?
9.6 Kb RNA virus, enveloped, Flavivridae family
Since there is no vaccine for HCV, we rely mostly on the broad acting antiviral {?}
Since there is no vaccine for HCV, we rely mostly on the broad acting antiviral Ribavirin
Explain how Ribavirin works
- Is a nucleoside analogue that is orignially inactive and then is activated by phosphorylation
- Blocks RNA synthesis (causes chain termination) by inhibiting IMP
It is very easy to get mutations that stop the functioning of Ribavirin, and so we now are using {?} to treat {?}
It is very easy to get mutations that stop the functioning of Ribavirin, and so we now are using DAAs (direct acting antivirals) to treat HCV (HepC)
Describe what DAAs are and their benefits
- Direct acting antivirals
- Relatively new class of medication
- Acts to target specitic steps in the HV viral lite cycle
- shorten the length of therapy, minimize side effects, target the virus itself, improve sustained virologic response (SVR) rate.
- structural and non-structural proteins - replicate and assemble new virions
- HCV - first chronic viral infection to be cured without IF or ribavirin.
Explain how DAAs work - what 3 things can they inhibit?
Inhibit:
- NS3/4 protease (needed for viral protein formation)
- NS5A (needed for assembly of virueses)
- NS5B polymerase (needed for RNA replication)
When talking about HCV, describe the genome and how we name the HCV (hep C) proteins
HCV is ssRNA
NS = non-structural protein
C = capsid
E = envelope
What is the function exactly of the viral protease in HCV
I beleive that the whole RNA genome is transcribed into one long protein which is then chopped up by this protease
What is post exposure prophylaxis?
The emergency management of exposure-prone incidents such as splashes of contaminated fluids, needle injuries etc.
Name some viral infections with no effective therapies
- rabies
- dengue
- common cold viruses
- ebola
- HPV
- arboviruses
- ‘Pathogen X’
