Anti-virals 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).
Acute infection (“Quick killers”) e.g. influenza; ebola; MERS; SARS
Chronic infection disease which we do not have vaccines for
- 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)
Acute inflammatory e.g. herpes
What are the current uses of anti-viral drugs?
Treatment of acute infection
- Influenza ; Chickenpox; herpes infections -(acyclovir)
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)
How do we induce the ‘selective toxicity’ that we need for anti-virals?
inhibit virus replication without harming the infected cell?
- Target protein in virus, not infected cell (if possible) - Due to the differences in structure and metabolic pathways between host and pathogen
What are the general stages of the virus life cycle?
Recognition and attachment which gets the virus into the cells
Penetration and uncoating which allow release of the viral genome
Replication via transcription and protein synthesis which gets us new viral DNA or RNA and new viral proteins which are then assembled into new viruses and released via budding or lysis
What are the different 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 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
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 are the different herpes viruses and antivirals?
Herpes viruses include:
- Herpes simplex (HSV),
- Varicella Zoster Virus (VZV)
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
Antivirals:
- acyclovir
IV/oral/topical
For HSV, VZV treatment/prophylaxis
CMV/EBV prophylaxis
- ganciclovir
IV/oral
For CMV
- Foscarnet
IV/local application
For CMV
- cidofovir
IV for CMVHow does acyclovir treat herpes virus induced diseases?
Herpes simplex - Treatment of encephalitis - Treatment of genital infection - suppressive therapy for recurrent genital herpes Varicella zoster virus - Treatment of chickenpox - Treatment of shingles - Prophylaxis of chickenpox CMV/EBV - Prophylaxis only
How is acyclovir selectively toxic?
Acyclovir is activated to active drug by a viral enzyme, thymidine kinase (TK), by increasing the number of phosphate residues of acyclovir
This makes acyclovir look like a DNA base and therefore the viral DNA polymerase incorporates only the active form of acyclovir into viral DNA
Accounts for low toxicity
Aciclovir triphosphate is a highly polar compound - difficult to leave or enter cells (but aciclovir is easily taken into cells prior to phosphorylation)
How does Ganciclovir treat CMV?
Active for CMV
- reactivated infection or prophylaxis in organ transplant recipients
- congenital infection in newborn
- retinitis in immunosuppressed
Structurally similar to acyclovir
CMV does not encode TK but has UL97 kinase
Inhibits CMV DNA polymerase
What is Foscarnet?
- Selectively inhibits viral DNA/RNA polymerases and RTs
- No reactivation 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)
What is Cidofovir?
- 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 do Herpes viruses develop resistance to anti-virals?
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)
What are the structural features of HIV?
A ds RNA genome bound by an enzyme called reverse transcriptase, responsible for turning the viral RNA into DNA
Two different layers of protein protection; the nuclear capsid and the matrix protein
You have a lipid membrane and spike proteins
What are the 7 steps in the life cycle of HIV?
- Attachment with binding of viral gp120 via Cd4 and CCRX
- Reverse transcription of RNA into dsDNA
- Integration into host chromosomes of pro-viral DNA
- Transcription of viral genes
- Translation of viral mRNA into viral proteins
- Virus assembly and release by budding
- Maturation
