W8 Mechanisms of action of antiviral drugs Flashcards
What are the common characteristics of viruses? (6)
- Smaller than bacteria and ACELLULAR agents
- Submicroscopic (different sizes and shapes)
- Obligate intracellular parasites (obliged to infect cells to use the cell machinery to reproduce)
- Do not grow or undergo division (outside cells)
- Are produced by replication from the assembly of pre-formed viral components
- Possess either DNA or RNA
Recap
What makes up a virus composition?
Virion or Virus particle
Covering:
- Capsid structure
- Envelope- not always present
Central core:
- Nucleic acids
(DNA or RNA)
- Matrix proteins/ enzymes (depends on the virus)
What are antiviral drug?
-A drug interfering selectively with the
virus replication (effective) without affecting the host cell (viable and safe).
-Inhibition of a viral life cycle step.
- Used to treat infections of specific
viruses, based on the mechanism
- No universal antiviral drug is available
What are the steps in the general virus life cycle? (6)
- Attachment- A generic virus becomes attached to a target epithelial cell
- Penetration- The cell engulfs the virus by endocytosis
- Uncoating- Viral contents are released
- Biosynthesis- Viral RNA enters the nucleus where it is replicated by the viral RNA polymerase
- Protein synthesis, protein maturation and virion assembly
- Release- New viral particles are made and released into the extracellular fluid. The cell, which is not killed in the process, continues to make a new virus
Virus-targeting vs Host-targeting agents
What is an example of a Cell host target?
What are its advantages and disadvantages?
Maraviroc (HIV) – It targets the human
CCR5 protein (blocking viral entry)
Advantages:
* Reduced risk of drug resistance
* Potential broad-spectrum effect (targeting multiple viruses)
Disadvantage:
* Reduced specificity (higher risk side effects)
Virus-targeting vs Host-targeting agents
What is an example of a Virus target?
What are its advantages and disadvantages?
Sofosbuvir (HCV) - nucleotide inhibitor class (inhibition of the viral polymerase)
Advantages:
* Potential selective toxicity towards the virus
* Potential limited/reduced toxicity
Disadv
* Risk of developing drug resistance
Mechanisms of action of antiviral agents
(for info)
Target: Viral attachment
moA= Entry inhibitor (Fostemsavir or HIBV)
Viral penetration= Fusion inhibitor (Enfuvirtide for HIV)
Viral uncoating= M2 blockers (Amantadine for Influenza virus)
Nucleos(t)ide analogs
Step 1 – Virus attachment inhibitors (HIV drugs)
What is the HIV entry mechanism?
Examples:
Virus target?
Cell-host target?
- HIV gp120 proteins bind to CD4
receptor on T-immune cells) - CD4 binding= enabling gp120 to
interact with a coreceptor protein
(CCR5 or CXCR4) of the host cell
Fostemsavir- targets the HIV gp120
-prevents its binding to CD4,
the cellular receptor
Maraviroc
* CCR5 antagonist,
* prevents the HIV-1 gp120/CCR5 interaction.
* It is not active with CXCR4-tropic HIV viruses
* Trofile test is needed to determine if HIV uses CCR5 or CXCR4
What are the HIV drugs?
Fostemsavir
Maraviroc
What is the moA of Fostemsavir?
(Virus target)
- targets the HIV gp120
- prevents its binding to CD4, the cellular receptor
What is the moA of Maraviroc?
(Cell-host target)
- CCR5 antagonist,
- prevents the HIV-1 gp120/CCR5 interaction.
- It is not active with CXCR4-tropic HIV viruses
- Trofile test is needed to determine if HIV uses CCR5 or CXCR4
Step 2 – Fusion inhibitors (HIV drug)
What occurs in this step?
Example of this drug?
Coreceptor binding induces insertion
of the gp41 fusion peptide into the
cell membrane
* This promotes fusion between the
viral envelope & host membranes
Enfuvirtide (Fuzeon)
* Peptide derived from gp41, to mimic components of the HIV-1 fusion machinery
* It binds to gp41, preventing the HIV envelope fusion with the cell membrane
Step 3 – Viral uncoating inhibitors virus
What occurs?
What are examples of M2 blockers?
SE? Why are they no longer reccomended?
- The influenza virus M2 protein is a proton channel embedded in the viral envelope
- Influenza virus entry activates the M2
- Protons enter the viral core= acidification
- Viral genome is released into the cell
M2 blockers (Amantadine and Rimantadine)
* They bind and block the M2 channel lumen
* Preventing virus uncoating
CNS side effects (hallucinations &confusion)
-99% of circulating influenza viruses are M2-resistant
- No longer recommended by BNF
- Amantadine has anti-parkinsonian unrelated effects -treats parkinsons
Step 4 – Viral genome replication
What do viruses use viral polymerase enzymes to do? (2)
Role of HIV reverse transcriptase? (3)
Viruses use viral polymerase enzymes and/or cellular enzymes to:
- Replicate their genome
- Transcription of viral genes to produce proteins= hijacking the host cell machinery
This step is virus-specific (DNA/RNA viruses or retrovirus like HIV)
HIV reverse transcriptase (RT)
* Performs reverse transcription= using single-stranded RNA genome to generate complementary DNA (cDNA)
* HIV cDNA can be integrated into the human DNA
* HIV cDNA is used by the cellular enzymes to transcribe RNA to produce viral proteins and replicate genome
Viral polymerase inhibitors represent the largest class of virus-targeting agents
Step 4 – Same basic polymerase principles
- Viral polymerases replicate viral genomes
- Incorporating complementary
triphosphate nucleotides based on the
template. - Synthesising nucleic acids from 5’ to 3’
- Forming phosphodiester bonds
between the 3ʹ end of the growing DNA
chain and the 5ʹ-phosphate group of the
incoming nucleotide
Viral genome replication inhibitors:
What are the 2 main types of inhibitors?
Nucleos(t)ide analogues or NRTI (HIV)
NON-nucleoside (NNRTI) HIV
Nucleos(t)ide analogues or NRTI (HIV)
What is the mechanism?
example drugs?
- Mimic and compete with the natural nucleotides to bind the enzymes active site
- Are incorporated into the growing nucleic acid chain
- Once incorporated, they terminate polymerase elongation
- Require activation by host/viral kinases, to the triphosphate form, to be active
Tenofovir and Abacavir
Features of NON-nucleoside (NNRTI) HIV:
- Do not resemble natural nucleotides
- Bind to viral polymerases at allosteric
sites, not the active site - Do not get incorporated into the nucleic acid chain.
- Allosteric inhibition= causing enzyme structure rearrangements and indirectly inhibit its function
- They don’t need activation steps.
Nucleotide Vs Nucleoside
Nucleo base (purine or pyrimidine)
Pentose sugar)
Nucleotide includes same but also addition of phosphate group(s)
Step 4:
What are nucleos(t)ide inhibitors:
- They are structurally similar to natural nucleo(t)ides
- Containing modifications to stop or impair the synthesis of nucleic acids
- Must be selective for viral polymerases (not the human one), reducing side effects
- When activated to the triphosphate form compete with the natural nucleotides to be incorporated into the growing nucleic acid chain
Must be selective for viral polymerases (not the human one), reducing side effects
Nucleos(t)ide inhibitors
Obligate Vs Non-obligate
What is the difference?
Examples?
Obligate:
-Lack 3’ OH (required for phosphodiester bond)
=Do not permit incorporation event
e.g. Aciclovir (ACV): HSV
mimicking guanosine
Non-Obligate
-Bearing 3’ OH and extra groups at 2’
or 4’ that sterically hinder the incorporation of the incoming NTP
e.g. Sofosbuvir (prodrug) HCV
mimicking uridine
Both are chain terminators
Nucleo(s)tide inhibitors:
Mutagenesis e.g. Ribavarin
What is this mechanism?
Ribavirin is not a chain terminator. Instead, they inhibit viral replication after mispairing with the template base, this is called mutagenesis.
Ribavirin (RBV) : (RSV, HCV, Lassa fever virus) mimicking guanosine (with modification in the nucleobase)
Step 4 – Nucleos(t)ide inhibitors activation
Acyclovir:
- Acyclovir is very selective and has a low cytotoxicity.
- Acyclovir is only converted into the mono-phosphate form by the viral thymidine kinase. Not active in uninfected cells. Not active in uninfected cells.
- Converted to the active form by cellular enzymes, acyclovir triphosphate has greater affinity (>100 fold) for the viral DNA polymerase
- Poor oral bioavailability, for oral use there is the prodrug valacyclovir
Step 4 – Nucleoside inhibitors (extra material)
Acyclovir
Penciclovir
Galanciclovir
Idoxuridine
Vidarabine
Trifluridine
Abacavir (ABC)
Telbivudine
Stavudine
Didanosine
Step 4 – Nucleos(t)ide inhibitors activation
What are the limitations of nucleosides analogues? (3)
- Slow activation to the monophosphate form (The first phosphorylation is the rate-limiting step)
- Rapid deactivation
- Active transport needed
Monophosphate Nucleotide/Protides
- Can bypass the first activation step(s)
- Poor cell penetration (charged).
- Masking the phosphate group is necessary (PROTIDE) to allow the intracellular delivery
ProTides
What are some properties of the blocking groups? (4)
What are some examples of licensed antiviral provides?
- Lipophilic
- Stable in plasma
- Hydrolyse in cells
- Byproducts non-toxic
Sofosbuvir (Solvaldi) HCV- Non-obligate chain terminator
Tenofovir alafenamide (Vemlidy), HIV, HBV
Remdesivir (Veklury)- Non-obligate chain terminator
Step 4 – NON-Nucleos(t)ide inhibitors:
- NNRTI structures are very different to nucleotides
- They exert a direct inhibition. No need for phosphorylation activation steps.
- ALLOSTERIC Inhibition (they do not target the active site
Step 4b - Integrase inhibitors (only of HIV)
Integrate is produced only by retroviruses (HIV), no human counterpart. HIV integrase is responsible for the establishment of viral latency (HIV infection is not curable.)
- HIV integrase insert the viral cDNA into the host chromosomes, by two steps:
A. 3’ processing - Cleaving two bases at the 3’ HIV DNA
B. Strand transfer - Viral cDNA is inserted into cell DNA - Mg2+ is a critical cofactor
E.g. Raltegravir, Elvitegravir, Dolutegravir, Bictergravir, Cabotegravir– block the strand transfer step of HIV DNA integration by chelating the Mg2+ in the active site
Suffix= Egravir
Step 5 –inhibition of protein synthesis & maturation:
Viral Protease inhibitors role?
- In many viruses (HIV, HCV, SARS-COV-2), the viral genome (not single genes) is fully translated into a single polyprotein precursor (immature).
- Viral proteases cleave viral polyprotein
precursors to form individual functional mature proteins (enzymes & structural capsid proteins)
How does Protease inhibition occur?(3)
- Protease inhibitors selectively bind to viral proteases stronger than natural substrate
- Peptidomimetics= Contain various non-cleavable groups to block their active site
- Inhibiting proteolytic cleavage* of polyprotein precursors into key proteins
*process of breaking peptide bonds between a.a in proteins
Peptidomimetics= small protein-like chain designed to mimic a peptide
Suffix of HIV and HCV Protease inhibitors? (for info)
HIV:
-NAVIR
e.g. Indinavir, Saquinavir, Lopinavir
HCV:
-PREVIR
e.g. Simeprevir, Paratiprevir
Step 6- Viral release inhibitors (influenza virus)
Influenza virus release & neuraminidase
What is the role of neuroamindase? (3)
- Neuraminidase is a viral enzyme of the envelope
- During virus budding, it hydrolises bonds between viral hemagglutinin and its cell receptor (sialic acid)
- Allowing virions to be released from infected cells
Neuraminidase inhibitors
MoA?
Monitoring points?
Suffix?
- Analogues of sialic acid, competing to bind to the neuraminidase and block the active site
- Preventing the release & spread of viral progenies
- Advised in patients at high risk of flu complications (pregnant females, immunosuppressed)
- Therapy must be started after 48 hours from the onset of symptoms
- Low but possible risk of drug resistance
Suffix = AMIVIR
Neuraminidase inhibitors:
What are they?
What is their suffix?
- Analogues of sialic acid, competing to bind to the neuraminidase and block the active site
- Preventing the release & spread of viral progenies
- Advised in patients at high risk of flu complications (pregnant females, immunosuppressed)
- Therapy must be started after 48 hours from the onset of symptoms
- Low but possible risk of drug resistance
AMIVIR
Non-nucleoside polymerase inhibitors are known for?
A) Directly binding to the viral polymerase active site
B) Acting as viral entry inhibitors
C) Targeting viral polymerase at allosteric sites
D) Requiring metabolic activation into the triphosphate form
E) Inducing mutations in the viral genome
=C
