Antivirals Flashcards
What antimicrobial drugs exits
- Antibiotics
- Anti-virals
- Anti-fungals
- Anti-protosoals
- Anti-helminths
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).
What are we currently using ant-viral drugs for
- Treatment of acute infection - acyclovir
- Treatment of chronic infection
- Post-exposure prophylaxis and preventing infection
- Pre-exposure prophylaxis
- Prophylaxis for reactivated infection:
How do antiviral drugs work
Induces selective toxicity without harming infected cells
- Target protein in virus, not infected cell
- Due to the differences in structure and metabolic
pathways between host and pathogen
What are 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
What are targets for anti-virals
- Thymidine kinase and HSV/VZV/CMV
- Protease of HIV
- Reverse transcriptase of HIV
- DNA polymerases
- Neuraminidase of influenza virus
Why is it difficult to develop effective non-toxic antiviral 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
What are often included with Herpes virus
- Herpes simplex (HSV)
- Varicella Zoster Virus (VZV)
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
What antivirals can be used for herpes virus
- Aciclovir
- Ganciclovir
- Foscarnet
- Cidofovir
How can Acyclovir be used for treatment of herpes
Herpes simplex:
- Treatment of encephalitis
- Treatment of genital infection
- suppressive therapy for
recurrent genital herpes
CMV/EBV:
- Prophylaxis only
Varicella zoster virus:
- Treatment of chickenpox
- Treatment of shingles
- Prophylaxis of chickenpox
Describe the mechanism of action of Aciclovir
Converted to active form by increasing the number of phosphate groups attached to it
Requires 2 viral enzymes:
- selectively activate ACV
- selectively inhibited
Resembles nucleotides and when used in viral DNA polymerase it causes chain termination
Why is acyclovir 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
Describe the mechanism if action of ganciclovir
Active for CMV:
- reactivated infection or prophylaxis in organ transplant recipients
- congenital infection in newborn
- retinitis in immunosuppressed
Structurally similar to aciclovir
CMV does not encode TK but has UL97 kinase
Inhibits CMV DNA polymerase
Describe how does foscarnet work
- Selectively inhibits viral DNA/RNA polymerases and RTs
- No reactivation is required
- Binds pyrophosphate binding site – a structural mimic
- used for CMV infection in the immunocompromised
e.g. pneumonia in solid organ and bone marrow transplants. - May be used because of ganciclovir resistance (TK mutants)
Describe hoe 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
How does resistance to herpes antivirals arise
They work in 2 main mechanisms:
- Thymidine Kinase mutants
- DNA polymerase mutants
If mutation occurs in TK, drugs not needing phosphorylation are still effective
(e.g. foscarnet, cidofovir)
- If it occurs in DNA polymerase, all drugs rendered less effective
- VERY RARE in immune competent patients (low viral load)
What types of anti-HIV drugs are there
- 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 Nucleoside reverse transcriptase (RT) inhibitors work
It is a 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
How does Non-nucleoside reverse transcriptase inhibitors work
Non-competitive inhibitor of HIV-1 RT
Synergistic with NRTI’s such as AZT because of different mechanism
What is given for post-exposure for HIV
- within 72 hours post-exposure
- take for 28 days
- 2x NRTIs + integrase inhibitor
What is given for Pre-exposure for HIV
- pre-exposure - blocks transmission
- 2x NRTIs (Truvada) two tablets 2
- 24 hours before sex, one 24 hours after intercourse and a further tablet 48 hours after intercourse
- called ‘on-demand’ or ‘event-based’ dosing
What is in the 2x NRTI treatment
Combination of Nucleoside RTIs emtricitabine (guanosine analog) and tenofovir (adenosine analog)
How does resistance to anti-virals come about
- Use of single agents leads to rapid development of
resistance - The drug binding site is altered in structure by as few as
one amino acid substitution - When mutation rate and viral load are high there is increased resistance to antivirals
How do viral quasispecies come about
- Selection pressure and mutation frequency
- Increased mutation rate seen in HIV
- They form a quasispecies within an individual patient: A viral swarm
- Reverse transcriptase lacks proofreading ability.
- All possible viral variants would be produced, hence the use of a combination of antivirals, e.g: HAART
