Mechanism Of Antivirals** Flashcards
What do antibiotics and anti-virals treat?
- Antibiotics = Treat bacteria
- Anti-virals = Treat virus
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 administration
State examples of infections or disease that require anti-viral drugs?
- Acute infection (“Quick killers”) e.g. influenza; ebola; MERS; SARS
- Chronic infection disease: hepatitis B [350,000,000 carriers], hepatitis C [200,000,000 carriers], human papilloma viruses, [cervical cancer, second commonest cancer in women]
- Human immunodeficiency virus (HIV): [40 million infected]
- Acute inflammatory e.g. herpes
State current uses of anti-viral drugs with examples of infections or diseases and the agent used (5)?
Standard infection
• Treatment of acute infection
• Influenza; Chickenpox; herpes infections - (aciclovir)
• Treatment of chronic infection:
- HCV, HBV, HIV (numerous different agents)
Prophalyxis
• Post-exposure prophylaxis and preventing infection:
- HIV (PEP)
• Pre-exposure prophylaxis: HIV (PrEP)
• Prophylaxis for reactivated infection: e.g. in transplantation - CMV (ganciclovir, foscarnet)
How do we induce ‘selective toxicity’ in anti-viral drugs as therapeutic agents?
- Selective toxicity = Inhibits virus replication without harming infected cell
- Occurs by
- Target protein in virus, not infected cell (if possible)
- Due to the differences in structure and metabolic pathways between host and pathogen
State the 9 general steps within the virus life cycle?
- Recognition
- Attachment
- Penetration
- Uncoating
- Transcription
- Protein synthesis
- Replication
- Envelopment
- Budding and release
State the 5 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
State common enzyme targets from anti-viral drugs and why?
- Thymidine kinase and HSV/VZVICMV
- Protease of HIV
- Reverse transcriptase of HIV
- DNA polymerases
- Neuraminidase of influenza virus
Why is it so difficult to develop effective, non-toxic, anti-viral drugs? (8)
- 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 aciclover target and specifically what treatments does it cover?
- Targets herpes virus (commonly characterised via muco-cuntaneous lesions - cold sores)
- Herpes viruses include: • Herpes simplex (HSV), • Varicella Zoster Virus (VZV) • Cytomegalovirus (CMV) • Epstein-Barr virus (EBV)
- Adminstered via IV/oral/tropical
What treatments does herpes simplex virus cover?
- Treatment of encephalitis
- Treatment of genital infection
- Suppressive therapy for recurrent genital herpes
What treatments does CMV/EBV cover?
Prophylaxis only
What treatments does Varicella Zoster Virus cover?
- Treatment of chickenpox
- Treatment of shingles
- Prophylaxis of chickenpox
What virus does ganciclovir, foscarnet and cidofovir target in relation to aciclover?
- Link between these are they all target herpes virus, but aciclover doesn’t excusively target CMV like these drugs do
- Herpes viruses include: • Herpes simplex (HSV), • Varicella Zoster Virus (VZV) • Cvtomegalovirus (CMV) • Epstein-Barr virus (EBV)
- ganciclovir: IV/oral, For CMV
- Foscarnet: IV/local application, For CMV
- Cidofovir: IV for CMV
Describe the selective toxicity of aciclover mechanism with the enzymes involved?
- Aciclover is activated to active drug within infected cell
- Requires 2 viral enzymes:
- Thymidine kinase (TK) = selectively activates ACV via phosphorylation to ACV triphophostae (activated drug)
- DNA polymerase = Selectively inhibited via drug
- Overall account for low toxicity of drug
Why is aciclovir so effective and safe?
- HSV thymidine kinase (TK) has 100x the affinity for ACV compared with cellular phosphokinases
- Acyclovir triphosphate has 30x the affinity for HSV DNA polymerase compared with cellular DNA polymerase.
- Acyclovir 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
State the uses of ganiclovir in CMV (3)
- Reactivated infection or prophylaxis in organ transplant recipients
- Congenital infection in newborn
- Retinitis in immunosuppressed
Describe briefly the mechanism of action of ganiclover? VD
- Active for CMV
- Structurally similar to aciclovir
- CMV does not encode TK but has UL97 kinase
- Inhibits CMV DNA polymerase
Describe the uses of Foscarnet
- 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 the mechanism of action for foscarnet
- Mechanism of action
- Selectively inhibits viral DNA/RNA polymerases and RTs
- No reactivation required
- Binds pyrophosphate binding site - a structural mimic
Describe the uses of cidofovir
- Drug active against CMV; but MUCH MORE nephrotoxic
- Treatment of retinitis in HIV disease
Describe the mechanism of action for cidofovir
- Mechanism of action
- Chain terminator
- Targets DNA polymerase
- Competes with dCTP
- Monophosphate nucleotide analog
- Prodrug - phosphorylated by cellular kinases to di-phosphate
Describe how resistance to anti-virals in herpes viruses occur?
- Two main mechanisms
- 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) - less likely for viral mutants to arise
Label the structural features of HIV from this diagram (make anki card for this manually)
- Envelope protein, g120 with transmembrane gp41
- Membrane associated matrix protein Gag 17
- Nucleocapsid protein Gag 24
- ds RNA genome
- Viral envelope
- Reverse transcriptase
State the 7 steps within the life cycle of HIV?
- Attachment with binding of viral gp120 via CD4 and CCRX
- reverse transcription of RNA into dsDNA
- Integration into host chromosome of proviral DNA
- Transcription of viral genes
- Translation of viral mRNA into viral proteins
- Virus assembly and release by budding
- Maturation
State the common targets for inhibitors of anti-HIV drugs (4)
- 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
State the key treatment for HIV?
- Highly Active Anti Retroviral Therapy
- HAART Combination of drugs to avoid resistance
Describe the mechanism of action behind nucleoside reverse transcriptase (NRTIs) inhibitors and state one example?
- Example: AZT-zidovudine
- Synthetic analogue of nucleoside thymidine - when converted to tri-nucleotide by cell enzymes, it blocks RT by (competitive inhibitor):
- Competing for natural nucleotide substrate dTTP
- Incorporation into DNA causing chain termination
- Others ddl, ddC, d4T, and 3TC (2’3’-dideoxy-3’-thiacytidine )???
Describe the mechanism of action behind non-nucleoside reverse transcriptase (NNRTIs) inhibitors and state one example?
- Example: Nevirapine
- Mechanism:
- Non-competitive inhibitor of HIV-1 RT -> terminates production of new viral genomes (don’t need to write this)
- Synergistic with NRTI’s such as AZT because of different mechanism
- Allows for resistance to occur
How does NNRTI’S and NRTI’s differ from one another?
The NNRTIs differ from the NRTIs in that they do not have a nucleotide structure and do not depend on phosphorylation for activity.
Describe the treatment for pre- (PrEP) and post-exposure
prophylaxis treatment for HIV?
- PEP - within 72 hours post exposure: Take for 28 days. 2x NRTIs + integrase inhibitor
- PrEP - 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
- 2 × NRTIs = Combination of Nucleoside RTIs emtricitabine (guanosine analog) + tenofovir (adenosine analog)
Describe how resistance to anti-virals can occur?
- Use of single agents leads to rapid development of resistance
- Causes the drug binding site is altered in structure by as few as one amino acid substitution
- If Mutation rate - high + Viral load - high (like HIV) -> resistance
How does HIV become resistant to anti-virals and describe how this can occur?
- Selection pressure and mutation frequency •
- Increased mutation rate seen in HIV. •
- They form a quasispecies within an individual patient:- A viral swarm (large number of different HIV viruses each with different genome content)
- The error rate in copying viral genome by reverse transcriptase enzyme is 1 base per 10 4-5 incorporations; lacks proof reading capacity. So, for HIV with 10 9-10 viruses produced every day, ALL possible viral variants would be produced (due to large error rate)
- Hence use of combinations of antivirals e.g. HAART
State 3 drugs that can be used to treat influenza with mechanism stated?
- Amantadine: Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin. Now rarely used
- Zanamivir and Oseltamivir (Tamiflu): Inhibits virus release from infected cells via inhibition of neuraminidase Oseltamivir -oral, Zanamivir- inhaled or IV - less likely for resistance to develop
Describe and state 2 examples and the mechanism of action of anti-flu drugs and the type of inhibitor they are?
- Anti’flu agents - Relenza - (zanamivir) and Tamiflu - (oseltamivir)
- 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
- NA = Neuraminidase inhibitors
State the mechanism and use of ribavirin?
- Ribavirin : nucleoside analogue
- Block RNA synthesis by inhibiting inosine 5’ monophosphate (IMP) dehydrogenase - this blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate) and thereby stops TP synthesis and, consequently, RNA synthesis
- Treat: RSV and HepC (in combination with pegylated interferon
State the use of direct-acting antivirals (DAAs) in what disease and how it affects it?
- 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 IN or ribavirin.
Describe the targets of Direct A-acting Antivirals in HCV?
- All the major HCV-induced enzymes - NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RNA-dependent RNA polymerase (RdRp) are essential for HCV replication and are potential drug targets.
- DAA with different viral targets, are synergistic in combinations
State exposure prone incidents and the prevention and management in occupational infection hazards?
- Exposure prone incidents : Sharps, Splashes and blood-born viruses
- Prevention - Universal Precautions
- Management: Emergency Management of exposure prone incidents
Describe the post-exposure prophyaxlis treatment for Hep B?
- Нер B
- Specific Hep B immunoglobulin (passive immunity) + vaccination within 48 hours (HBV treatment includes antivirals 3TC/NRTIs)
Describe the post-exposure prophyaxlis treatment for Hep C?
- Interferon-gamma + ribavarin (anti-viral) for 6 months within first 2 months of exposure 90% cure rate
- Now direct acting antivirals
Describe the post-exposure prophyaxlis treatment for HIV?
- HIV
- 80% protection i.e. no sero-conversion must be FAST - hours antiviral drug treatment - 28 days 2xNRTI + protease or integrase inhibitor
State examples of viral infection with no effective therapies (6)?
- Rabies virus
- Dengue
- Common cold viruses
- Ebola
- HPV
- Arbovirsues
