L9 - Mechanism of Antivirals Flashcards
Why do we need Anti-viral drugs?
There are no or poorly effective 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).
Describe the current uses of Anti-viral drugs?
Treatment of acute infection
Influenza ; Chickenpox; herpes infections -(aciclovir)
Treatment 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
CMV (ganciclovir, foscarnet)
What are the principles of Anti-viral drugs as therapeutic agents?
Selective Toxicity must be induced
inhibit virus replication without harming the host cell:
Target protein in virus, not infected cell (if possible)
Due to the differences in structure and metabolic pathways between host and pathogen
What might be the modes of action of selected Anti-virals?
Preventing virus adsorption onto host cell
Preventing penetration
Preventing viral nucleic acid replication (nucleoside analogues)
Preventing maturation of virus
Preventing virus release
Why is it difficult to develop effective, non-toxic Anti-viral drugs?
- 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
How is Aciclovir useful in the treatment of Herpes Simplex?
Treatment of encephalitis
Treatment of genital infection
suppressive therapy for recurrent genital herpes
How is Aciclovir useful in the treatment of Varicella Zoster virus?
Treatment of chickenpox
Treatment of shingles
Prophylaxis of chickenpox
How is Aciclovir useful in the treatment of CMV/EBV?
Prophylaxis
Describe how Aciclovir works?
only works in virus infected cells. It is administered into infected cell in its inactive form.
This inactive form is then modified into an active form, via a viral enzyme (viral thymidine kinase). It activates the Aciclovir by adding more phosphate residues, making it seem like a DNA base.
Viral DNA polymerase, incorporates only the active form into viral DNA.
Has a very low toxicity
Why is Aciclovir a safe and effective Anti-viral?
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
What are 2 mechanisms by which resistance to Aciclovir in Herpes Virus can occur and why is it rare?
Thymidine Kinase mutants
DNA polymerase mutants
If occurs in TK, drugs not needing phosphorylation are still effective (e.g. foscarnet, cidofovir)
If occurs in DNA polymerase, all drugs rendered less effective
VERY RARE in immune competent patients (low viral load)
What are some different types of Anti-HIV drugs?
Anti-reverse transcriptase inhibitors
nucleoside/nucleotide RT inhibitors
non-nucleotide RT inhibitors (allosteric)
- 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 - Highly Active Anti Retroviral Therapy HAART
Combination of drugs to avoid resistance
How does Zidovudine work?
It is a reverse transcriptase inhibitor.
Synthetic analogue of nucleoside thymidine –
when converted to tri-nucleotide by cell enzymes, it blocks RT by
- competing for natural nucleotide substrate dTTP
incorporation into DNA causing chain termination
Give an example of a non-nucleoside reverse transcriptase inhibitor for HIV?
Nevirapine
Describe how there is resistance to Antivirals in HIV?
The drug binding site is altered in structure by as few as one amino acid substitution
Mutation rate - high
Viral load – high
resistance
How does Amantadine work for Influenza?
Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin
Now rarely used
How does Zanamivir work for Influenza?
Inhibits virus release from infected cells via
inhibition of neuraminidase
Oseltamivir –oral
Zanamivir- inhaled or IV - less likely for resistance to develop
How does Ribavirin work for Hepatitis C
Block RNA synthesis by inhibiting inosine 5’-monophosphate (IMP) dehydrogenase –
this blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate)
and thereby stops GTP synthesis and, consequently, RNA synthesis
What are DAA’s and what do they do?
Direct acting antivirals
relatively new class of medication
acts to target specific steps in the HCV viral life 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 IFN or ribavirin
State some viral infections that are not treatable?
- rabies
- dengue virus
- common cold virus
- ebola
- HPV
- Arboviruses
