Mechanisms of action 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)
What are the current use of anti-viral drugs?
→Treatment of acute infection →Treatment of chronic infection →Post-exposure prophylaxis and preventing infection-HIV →Pre-exposure prophylaxis →Prophylaxis for reactivated infection
Examples of acute infections treated with anti-viral drugs
→Influenza
→Chickenpox
→herpes infections
What drug is used to treat influenza, chickenpox, and herpes?
→aciclovir
What chronic infections are treated with antivirals?
→HCV,
→HBV,
→HIV
What viral disease cab be reactivated and what drug is used to treat it?
→CMV
→ganciclovir
How do we induce selective toxicity?
→Target protein in virus, not infected cell
→Due to the differences in structure and metabolic pathways between host and pathogen
Summarise virus life cylce
→recognition →attachment →penetration →uncoating →transcription →protein synthesis →replication →assembly →lysis and release
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 is the mechanism of action of Amantadine?
→blocks low pH endosome dependent on coating M2 protein
→influenza A
What doe HIV protease inhibitors work?
→block protein synthesis
What is the mechanism of action of Zanamivir?
→blocks viral release
What is the mechanism of action of viral interferons?
→blocks viral mRNA translation
What is the mechanism of action of AZT?
→blocks HIV reverse transcriptase to prevent formation of dsDNA provirus from the HIV RNA genome
What do acyclovir, ganciclovir, and ribavarin have in commom?
→inhibit nucleic acid polymerisation
What are some commonly used anti-viral drugs targets?
→Thymidine kinase and HSV/VZV/CMV
→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 ?
→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
→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 virus causes these muco-cutaneous lesions ?
→Herpes viruses
What are the different herpes viruses?
→Herpes simplex (HSV),
→Varicella Zoster Virus (VZV)
→Cytomegalovirus (CMV)
→Epstein-Barr virus (EBV)
What does ganciclovir treat?
→IV/oral
→For CMV
What does foscarnet treat?
→IV/local application
→For CMV
What does cidofovir treat?
→IV for CMV
How is aciclovir used to treat CMV/EBV?
→Prophylaxis only
How is aciclovir used to treat herpes simplex?
→Treatment of encephalitis
→Treatment of genital infection
→suppressive therapy for recurrent genital herpes
How is aciclovir used to treat VZV?
→Treatment of chickenpox
→Treatment of shingles
→Prophylaxis of chickenpox
How does aciclovir work?
→Activated by Thymidine kinase by increase number of phosphate residues in aciclovir
→Looks like DNA base so viral DNA incorporates acyclovir
→chain termination
Why is aciclovir 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
What is the mechanism of action of ganciclovir?
→Inhibits CMV DNA polymerase
What structure is acyclovir similar to?
→guanosine
What are diseases ganciclovir used for?
→reactivated infection or prophylaxis in organ transplant recipients
→congenital infection in newborn
→retinitis in immunosuppressed
What is ganciclovir similar to?
→aciclovir
What does CMV encode which is similar to TK in function?
→has UL97 kinase
When might foscarnet be used?
→because of ganciclovir resistance (TK mutants)
Describe mechanism of action of foscarnet
→Selectively inhibits viral DNA/RNA polymerases and RTs
→No reactivation required
→Binds pyrophosphate binding site – a structural mimic
What virus is foscarnet used to treat?
→CMV infection in the immunocompromised
How does cidoforvir work?
→Chain terminator - targets DNA polymerase
Competes with dCTP
Monophosphate nucleotide analog
What type of drug is cidofovir?
→prodrug
→phosphorylated by cellular kinases to di-phosphate
What is cidofovir used to treat?
→drug active against CMV; but MUCH MORE nephrotoxic
Treatment of retinitis in HIV disease
What are the two main ways viruses become resistant to antivirals?
→Thymidine Kinase mutants
→DNA polymerase mutants
What can be done if resistance occurs in Thymine Kinase?
→drugs not needing phosphorylation are still effective (e.g. foscarnet, cidofovir)
What happens if resistance occurs in DNA polymerase?
→all drugs rendered less effective
What are the structural features of HIV?
→Envelope protein, gp120 with transmembrane gp41 →Membrane- associated matrix protein Gag 17 →Nucleocapsid protein Gag p24 →ds RNA genome →Viral envelope →Nucleocapsid protein Gag p24 →ds RNA genome
Describe the life cycle of HIV
→Attachment with binding of viral gp120 via CD4 and CCRX →2. reverse transcription of RNA into dsDNA →3. Integration into host chromosome of proviral DNA →4. Transcription of viral genes →5. Translation of viral mRNA into viral proteins →. Virus assembly and release by budding →7. maturation
What are the types of anti-HIV drugs?
→Anti-reverse transcriptase inhibitors
→Protease inhibitors
→Integrase inhibitors
→ Fusion inhibitors- gp120/41 - biomimetic lipopeptide
→Highly Active Anti Retroviral Therapy HAART
What are the two types of anti-reverse transcriptase inhibitors?
→nucleoside/nucleotide RT inhibitors
→ non-nucleotide RT inhibitors (allosteric)
How do nucleoside reverse transcriptase inhibitors work?
→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 do non-nucleoside reverse transcriptase inhibitors work?
→Non-competitive inhibitor of HIV-1 RT
→Do not look like DNA bases
Gets incorporated into viral DNA by RT- terminates production of new viral DNA
→Synergistic with NRTI’s such as AZT because of different mechanism
What are post exposure prophylaxis for HIV?
→PEP – within 72 hours post exposure - take for 28 days.
2x NRTIs + integrase inhibitor
What are pre- exposure prophylaxis for HIV?
→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 two factors lead to viral resistance to drugs?
→Mutation rate - high
→Viral load – high
What events lead to viral swarm?
→Selection pressure and mutation frequency
→Increased mutation rate seen in HIV.
→They form a quasispecies within an individual patient
How does amantadine work?
→Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin
How do zanamivir and Oseltamivir work?
→Inhibits virus release from infected cells via inhibition of neuraminidase
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
What is influenza still sensitive to?
→zanamivir
How is Hep C commonly transmitted?
→via blood – infectious (mother to baby)
What is Hep C a major cause of?
→chronic liver disease
What is the incubation length of Hep C?
→1 - 6 months
What family of viruses does Hep C belong to?
→enveloped; Flaviviridae family
How does ribavirin?
→Block RNA synthesis by inhibiting inosine 5’-monophosphate (IMP) dehydrogenase –
→blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate)
→thereby stops GTP synthesis and, consequently, RNA synthesis
What does ribavirin treat?
→RSV
→HepC
→combination with pegylated interferon
What are advantages of direct-acting antivirals?
→shorten the length of therapy,
→minimize side effects,
→target the virus itself,
→improve sustained virologic response (SVR) rate
Describe the mechanism of action of direct-acting antivirals
→block replication complex formation assembly
What are the major Hep C induced viruses?
→NS2-3 and NS3-4A proteases
→NS3 helicase and NS5B
What is the post-exposure prophylaxis for Hep B?
→specific Hep B immunoglobulin (passive immunity)
→+ vaccination
→within 48 hours
What is the post-exposure prophylaxis for Hep C?
→interferon-gamma + ribavarin (anti-viral) for 6 months
→within first 2 months of exposure
→90% cure rate
What is the post-exposure prophylaxis for HIV?
→80% protection i.e. no sero-conversion
→must be FAST – hours
→antiviral drug treatment – 28 days
→2xNRTI + protease or integrase inhibitor
Examples of the incurables viruses
→rabies →dengue →Common cold viruses →Ebola →HPV →Arbovirsues
