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
Describe how amantadine works against influenza virus
Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin
Now rarely used
Describe how does Zanamivir and Oseltamivir (Tamiflu)
work against influenza virus
- Inhibits virus release from infected cells via
inhibition of neuraminidase - Oseltamivir - oral
- Zanamivir - inhaled or IV, less likely to develop resistance
How do neuraminidase inhibitors work
- target and inhibit NA at highly conserved site (reduce chances of resistance via mutation)
- prevent release of sialic acid residues from the cell receptor
- preventing virus budding and release and spread to adjacent cells
How does ant-viral resistance occur in influenza
- Resistance sometimes only requires a single amino acid change - seen recently with swine flu (H1N1) and
Tamiflu (oseltamivir) - Point mutation (H275Y; tyrosine replacing histidine)
- Seen in immunocompromise patients; shed virus for weeks/months
- Likely to be selected from among quasispcies during treatment
- Transmissible and virulent
- Remains sensitive to zanamivir
What is Hepatitis C
- 9.6 Kb RNA virus, enveloped; Flaviviridae family; identified in 1989
- transmitted via blood – infectious (mother to baby)
- increasingly common – high risk groups – drug users 20% +ve; – needles (sex?)
- major cause of chronic liver disease
- occupational risk groups – healthcare workers
- needle-stick risk – 3% to sero-conversion; chronic carriage almost certain (85%) * long incubation – 1 - 6 months
- vaccination NOT available
How does the nucleoside analogue ribavirin work
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
Has to be activated by being phosphorylated with the help of ATP
How do Direct-acting antivirals work against hepatitis C
- 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.
What is seen as an occupational injection hazards
- Exposure-prone incidents
- Sharps, splashes and blood-borne viruses
Prevention - Universal precautions
Management - Emergency management of exposure prone incidents
What is given as post-exposure prophylaxis treatment for Hep B
specific Hep B immunoglobulin (passive immunity) + vaccination within 48 hours (HBV treatment includes antivirals 3TC/NRTIs)
What is given as post-exposure prophylaxis treatment for Hep C
interferon-y + ribavarin (anti-viral) for 6 months within first 2 months of exposure 90% cure rate - now direct acting antivirals
What is given as post-exposure prophylaxis treatment for HIV
80% protection i.e. no sero-conversion must be FAST – hours antiviral drug treatment – 28 days 2xNRTI + protease or integrase inhibitor
What are classified as incurables
- rabies
- dengue
- Common cold viruses
- Ebola
- HPV
- Arbovirsues
- “Pathogen X”
