Mechanisms of Anti-virals Flashcards
1
Q
Why do we need anti-virals?
A
- Some viruses kill quickly
- Influenza, Ebola, MERS, SARS
- Some viral infections can be slow and progressing chronic infections leading to cancer
- HepB, HepC, HPV (can cause cervical cancer)
- Some viral infections are highly infectious such as HIV
- Acute inflammatory diseases e.g Herpes
2
Q
Give some examples of anti-microbials
A
Antibiotics (target bacteria), antivirals, anti-fungals, anti-protosoals, anti-helminths.
3
Q
What are some uses of anti virals?
A
-
Treatment of acute infection
- Infuenza, chickenpox, shingles, 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. transplantation, CMV (ganciclovir, forscarnet)
4
Q
What is selective toxicity?
A
When a drug has a selective action against one component and not another
5
Q
Elaborate on selective toxicity
A
- Is achieved due to differences in structure and metabolic pathways between host and pathogen
- It harms the microorganisms, not the host
- We want the target to be in the microbe (not host) if possible
- Difficult for viruses as they are intracellular and use cellular processes to replicate themselves
- Variation between microbes (even strains of same species)
- E.g HIV has a high mutation rate as no DNA repair mechanism
6
Q
Why is it difficult to develop effective, non-toxic anti-viral drugs?
A
- Virus may enter the cells using cellular receptors which may have other functions
- Viruses must replicate inside cells → obligate intracellular parasites
- Viruses take over host cell replicative machinery
- Viruses = HIGH MUTATION RATE → Quasispecies
- Anti-virals must be selective in their toxicity
- Should only exert their action on infected cells
- Some viruses can remain in a latent state e.g Herpes
- Some viruses are able to integrate their genome into the host genome
7
Q
Provide a recap of the virus life cycle
A
- Virus will attach itself to the membrane and internalise via membrane fusion (remember HIV glyprotein fusion) or endocytosis
- Virus will then uncoat, removal of capsid and release its genome
- The genome will replicate itself and make mRNA which will enter the ribosomes of the cell and make viral proteins
- The newly synthesised viral proteins will assemble at the membrane = new virus particle
- The processed and assembled virus will exit the cell via budding through the membrane
- Some viruses will assemble inside the cell and escape via cell lysis
8
Q
What are some considerations when developing safe anti-viral agents?
A
- Cellular receptor may have other important functions
- Viral enzymes may be very similar to host
- Blocking cellular enzyme may kill the cell
9
Q
What is the mode of action of selected anti-virals?
A
- Preventing virus adsorption onto host cell
- Preventing penetration
- Preventing viral NA replocation (through nucleoside analogue, usually a terminator)
- Preventing virus maturation
- Preventing virus release
10
Q
What is the mode of action of selected anti-virals?
A
- Amantadine → blocks the uncoating process in the influenza A virus,however not used anymore because it had toxicity associated with it).
- Acyclovir, Ganciclovir, Ribavarin → Inhibit NA polymerisation by inhibiting reverse transcriptase’s or DNA polymerases
- Zidovudine/Azidothymidine (AZT) → thymidine analogue, selectively inhibits HIV’s reverse transcriptase
- Ribavarin → Acts as an analogue of GTP, compromises the genome replication
- Protease inhibitors → Block particle maturation
- Zanamivir → Is an anti influenza drug, blocks the mature release of the particle from the cell
11
Q
List some selective toxicity viral targets
A
- Thymidine kinases of HSV/VZV/CMV
- Proteases of HIV
- Reverse transcriptases of HIV
- DNA polymerases
- Neuraminidases of Influenza virus
12
Q
List the herpes viruses
A
- Herpes simplex (HSV)
- HSV1 causes muco-cutuneous lesions on the lip
- Varicella zoster virus (VZV)
- Cytomegalovirus (CMV)
- Epstein-Barr Virus (EBV)
13
Q
List some drugs for treating herpes viruses
A
- Aciclovir → for HSV, VZV treatment, prophylaxis of CMV
- Ganciclovir → for CMV
- Foscarnet → for CMV
- Cidofir → for CMV
14
Q
What are other anti-herpes virus agents? Foscarnet
A
Foscarnet - also treats CMV
- Selective inhibits viral DNA/RNA polymerases by competing with pyrophosphate
- Binds to pyrophosphate binding site à structural mimic
- No reactivation required (not a prodrug like aciclovir and ganciclovir)
- 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)
15
Q
What is aciclovir?
A
Acycloguanosine analogue (GTP analogue), has a missing 3’ OH acting as a chain terminator, is inserted into DNA and prevents it from replicating
Competitive inhibitor of viral DNA polymerase, competes with standard GTP
16
Q
What is the mechanism of action of aciclovir?
A
- First it has to be activated by viral thymidine kinases
- It will then be phosphorylated by cellular guanylate GDP kinases = remains stable in the cell
- Once it has been tri phosphorylated = active drug
- Competitve inhibitor for viral DNA polymerase, it competes for standard GTP preventing viral polymerase from synthesising viral genome
22
Q
What is the mechanism of action of gangciclovir?
A
- Gangciclovir will be phosphorylated by UL97 kinase gene encoded in the CMV genome
- It will then be diphosphorylated and triphosphorylated inside the cell via cellular kinases
- It then has the same effects as aciclovir by competitive inhibition
- Similar to ACV it will compete for the natural substrate DNA polymerase and block the abillity to make its own DNA
25
Q
What is the structure of HIV?
A
- Double stranded RNA genome encaspulated by nucleocapsid (Gag p24)
- Outer layer consists of lipid bilayer consisting of protuding protein spikes which mediate entry into cell
- Envelope glycoproteins gp120 (receptor ligand) and gp41 (transmembrane)
- Inside envelope lie Gag proteins (membrane associated matrix protein Gag 17)
- Virus will encode particular viral enzymes
- Integrase
- Protease
- Reverse Transcriptase
26
Q
Describe the steps in the HIV life cycle
A
- Attachment with binding of viral gp120 via CD4 and CCRX
- Reverse transcription of RNA into dsDNA
- DNA provirus integrates into host chromosome
- Transcription of host viral genes which form mRNA
- Translation of mRNA to make viral proteins or regeneration of RNA to form the genome in new virus particle
- Virus assembly and release by budding
- Post-release maturation
35
Q
Describe ZANAMIVIR AND OSELTAMIVIR (TAMIFLU) as an anti-viral combating influenza
A
- Inhibits virus release from infected cells via inhibition of neuraminidase → PREVENTS BUDDING FROM THE CELL
- Cleaves salic acid from receptor allowing virus to be released
40
Q
Describe the mechanism of action of ribavarin
A
- Blocks RNA synthesis by inhibiting inosine 5’ monophosphate (IMP) dehydrogenase
- This normally converts IMP to XMP (xanthosine 5’-monophosphate)
- This thereby stops GTP synthesis and consequently RNA synthesis
- Treats RSV nd HepC (in combination with pegylated interferon)
41
Q
Describe direct acting antivirals
A
- 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 (cleared the virus completely) without IFN or ribavirin.
