Mechanism of antivirals Flashcards
Why do we need anti-virals?
→ Quick killers
* e.g. influenza; ebola; MERS; SARS, SARS-CoV-2
* Slowly, progressive chronic disease leading to cancer
→ Hepatitis B [350 million carriers]
→ Hepatitis C [200 million carriers]
→ Human papilloma viruses
* [cervical cancer, second commonest cancer in women]
→ Human immunodeficiency virus (HIV)
* [40 million infected]
→ Acute inflammatory e.g. Herpes
How can we use antivirals? (What can we use antivirals for?)
For Treatment of acute infection
– Influenza ; Chickenpox; shingles - herpes infections -(aciclovir)
- For Treatment of chronic infection:
– HCV, HBV, HIV (numerous different agents) - used in Post-exposure prophylaxis and preventing infection:
– HIV (PEP) - used for Pre-exposure prophylaxis: HIV (PrEP)
- used for Prophylaxis for reactivated infection: e.g. in transplantation
– CMV (ganciclovir, foscarnet)
What principle/concept is important to abide by when developing antivirals as therapeutic agents?
Selective Toxicity is an important concept:
→ Agents need to be toxic against but not the host in the process - ie us
→ Due to the differences in structure and metabolic pathways between host and pathogen
→ Antivirals must Harm microorganisms, not the host
→ Target in microbe, not host (if possible)
→ Difficult for viruses (intracellular), fungi and parasites
→ Variation between microbes and resistance
Why is it so difficult to develop
Effective, non-toxic anti-viral drugs ?
→ Viruses enter cells using cellular receptors which may have other functions
→ Viruses must replicate inside cells – obligate intracellular parasites
→ Viruses take over the host cell replicative machinery
→ Some 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 generally, overall happens in the life cycle of a virus?
overall summary:
- Recognition
- Attachment
- Penetration (or fusion)
- Uncoating
- Transcription to make viral proteins eventually
- Protein synthesis
- Replication
- Envelope
- Budding and release or lysis and release
What are examples of modes of action of selected antivirals?
what is an example of a drug that can be used for these modes of action?
→ Preventing virus adsorption onto host cell
→ Preventing penetration of viruses into the cell
→ Preventing viral nucleic acid replication (nucleoside analogues)
→ Preventing maturation of virus (i.e. preventing re assembling of virus)
→ Preventing virus release
Drug name: amantadine
Function: Blocks the un-coating of a virus so it can’t un-coat and replicate etc in the cell to cause damage however it is not used so much now as it is toxic
Drug examples: acyclovir, ganciclovir and ribavarin
Function: inhibit RNA polymerase to inhibit genome replication of the virus once it is inside and uncoated in the cell
Drug name: AZT
Function: Blocks HIV reverse transcriptase to prevent formation of dsDNA provirus from the HIV RNA genome
Drug example: Ribavarin
Function: Prevent the virus making its messenger RNA to go on to make its proteins
Use: to treat respiratory complications
Drug name: Zanamivir
Function: Blocks the release of the virus from the cell
What are examples of some selective toxicity viral agents?
→ Thymidine kinase and HSV/VZV/CMV
→ Protease of HIV
→Reverse transcriptase of HIV
→ Viral DNA polymerases
→ Neuraminidase of influenza virus
What are some examples of ‘herpes viruses’? What drug can be used for certain ones?
Herpes viruses include:
* Herpes simplex (HSV),
* Varicella Zoster Virus (VZV)
* Cytomegalovirus (CMV)
* Epstein-Barr virus (EBV)
- aciclovir (remember this one!)
IV/oral/topical
For HSV, VZV
treatment/prophylaxis
CMV/EBV prophylaxis
However, aciclovir doesn’t work particularly well in treating Cytomegalovirus (CMV), so there is aloso:
- ganciclovir
IV/oral
For CMV - Foscarnet
IV/local application
For CMV - cidofovir
– IV for CMV
How does aciclovir work?
→ You have acylcoguanosine which gets partially activated by viral Thymidine Kinase (TK)
→ Then becomes di and tri-phosphorylated by cellular guamylate/GDP kinases
→ It now is in the active form of aciclovir and is active to inhibit viral DNA Polymerase (by chain termination)(which is MUCH more sensitive to activated aciclovir than human polymerases)
Requires 2 viral enzymes
= selectively activate ACV (acyclovir triphosphate?)
= selectively inhibited
→ This accounts for the low toxicity of aciclovir
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 does ganciclovir do?
Problem isnt necessarily the cytomegalovirus (flu like virus) but it’s an issue in immunocompromised people
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 (thymidine kinase) but has UL97 kinase- which activates ganciclovir
* Inhibits CMV DNA polymerase
ganciclovir gets into the cell because its non-polarised and gets activated by UL97, then gets di and tri phosphorylated by cellular kinases then the active form can inhibit the CMV DNA polymerases which are encoded by a gene called ul54
What other anti-herpes virus agents can be used to treat CMV? (cytomegalovirus)
- Foscarnet:
– Selectively inhibits viral DNA/RNA polymerases- BUT NOT BY COMPETING FOR THE SUBSTRATE LIKE ACICLOVIR AND GANCICLOVIR - BUT BY ACTING AS AN ALLOSTERIC INHIBITOR
– 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 (UL97 mutants) - 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
What are the 2 main mechanisms for developing resistance to anti-virals in Herpes viruses?
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
- Viral resistance is VERY RARE in immune competent patients (low viral load)
What are some structural features of the human immunodeficiency virus?
Envelope protein, gp120 with transmembrane gp41
Membrane associated matrix protein Gag 17
dsRNA genome
Viral envelope
Nucleocapsid protein Gag p24
Reverse transcriptase
Name 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 chromosome of proviral DNA
- Transcription of viral genes
- Translation of viral mRNA into viral proteins
- Virus assembly and release by budding
- Maturation.
