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Molecular Basis of Disease and Microbiology and Immunology > Mechanism of Antivirals > Flashcards

Mechanism of Antivirals Flashcards

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Biology 101 flashcards
1
Q

Why do we need anti-virals?

A

• 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

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2
Q

How can we use antivirals? (What can we use antivirals for?)

A

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)

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3
Q

What principle/concept is important to abide by when developing antivirals as therapeutic agents?

A

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
  • Antiviral 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
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4
Q

Why is it so difficult to develop

effective, non-toxic anti-viral drugs ?

A

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

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5
Q

What generally, overall happens in the life cycle of a virus?

A

overall summary:

  1. recognition
  2. attachment
  3. penetration (or fusion)
  4. uncoating
  5. transcription to make viral proteins eventually
  6. protein synthesis
  7. replication
  8. envelope
  9. budding and release or lysis and release
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6
Q

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?

A

• 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

eg amantadine is an example of a drug that blocks the uncoating 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

also have drugs that inhibit rna polymerase to inhibit genome replication of the virus once it is inside and uncoated in the cell eg acyclovir, ganciclovir and ribavarin

also a drug called AZT- blocks HIV reverse transcriptase to prevent formation of dsDNA provirus from the HIV RNA genome

also drugs that prevent the virus making its messenger RNA to go on to make its proteins etc - eg ribavarin, used to treat respiratory complications

also have drugs that block the release of the virus from the cell eg Zanamivir

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7
Q

What are examples of some selective toxicity viral agents?

A
  • Thymidine kinase and HSV/VZV/CMV
  • Protease of HIV
  • Reverse transcriptase of HIV
  • Viral DNA polymerases
  • Neuraminidase of influenza virus
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8
Q

What are some examples of ‘herpes viruses’? What drug can be used for certain ones?

A 
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
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9
Q

How does aciclovir work?

A

You have acylcoguanosine which gets partially activated by viral Thymidine Kinase (TK) and 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

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10
Q

Why is aciclovir so effective and safe?

A

• 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

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11
Q

What does ganciclovir do?

A

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

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12
Q

What other anti-herpes virus agents can be used to treat CMV? (cytomegalovirus)

A

• 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

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13
Q

What are the 2 main mechanisms for developing resistance to anti-virals in Herpes viruses?

A

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)

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14
Q

What are some structural features of the human immunodeficiency virus?

A

Envelope protein, gp120 with transmembrane gp41

Membrane associated matrix protein Gag 17

ds RNA genome

viral envelope

Nucleocapsid protein Gag p24

reverse transcriptase

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15
Q

Name the 7 steps in the life cycle of HIV

A
  1. 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
  6. Virus assembly and release by budding
  7. maturation
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16
Q

What categories can anti-HIV drugs be put into?

A
  1. Anti-reverse transcriptase inhibitors
    • nukes -nucleoside/nucleotide RT(reverse transcriptase) inhibitors
    • non-nukes -non-nucleotide RT inhibitors (allosteric)
  2. Protease inhibitors - multiple types
  3. Integrase inhibitors – POL gene - protease, reverse transcriptase and integrase (IN)
    with the 3´end encoding for IN (polynucleotidyl transferase) (so if we block this IN, we have this antiviral that blocks the integration of the HIV genome into the host genome)
  4. Fusion inhibitors – gp120/41 - biomimetic lipopeptide (many other types)- these try to block the virus from fusing to the surface of the cell,

We always use the above in a combination of 3 usually- which we call this treatment method:
- HAART- highly active anti retroviral therapy
Combination of drugs to avoid resistance

17
Q

What does the anti-HIV drug AZT - Zidovudine do?

A

AZT is a nucleoside analogue- it is a nuke

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

18
Q

What does a non-nuke like Nevirapine do/what do we know?

A

Non-nuke, non competitive inhibitors

Non-competitive inhibitor of HIV-1 RT (reverse transcriptase- copies RNA into DNA)
Synergistic with NRTI’s (Nucleotide reverse transcriptase inhibitors) such as AZT because of different mechanism

19
Q

If exposed to HIV, how does pre and post-prophylaxis work?

A

if exposed to HIV, can take PEP (post exposure prophylaxis)– within 72 hours post exposure - take for 28 days.
This consists of 2x NRTIs + integrase inhibitor (immediately blocking the ability of the virus to reverse transcribe its DNA and also blocking the integration of the pro viral DNA to the host genome

PrEP – pre-exposure - (eg if engaging in unprotected sex) blocks transmission
can take 2x NRTIs (Truvada)
two tablets 2 – 24 hours before sex, one 24 hours after sex and a further
tablet 48 hours after sex - called ‘on-demand’ or ‘event based’ dosing

These 2 x NRTIs comprise of:
Combination of Nucleoside RTIs
emtricitabine (guanosine analog) 
\+ 
tenofovir (adenosine analog)
20
Q

Why do treatments tend to be a combination for targeting HIV?

A
  • Use of single agents leads to rapid development of resistance
  • The drug binding site is altered in structure by as few as one amino acid substitution

• A high Mutation rate + high Viral load → resistance

• Selection pressure and mutation frequency
• Increased mutation rate seen in HIV.
• They form a quasispecies within an individual patient:-
A viral swarm
• The error rate in copying viral genome by reverse transcriptase
enzyme is 1 base per 10 4-5
incorporations; lacks proof reading
capacity. So, for HIV with 10 9-10 viruses produced every day,
ALL possible viral variants would be produced
• Hence use of combinations of antivirals
e.g. HAART

21
Q

What drugs can be used to target the influenza virus? What do they do?

A

• Amantadine
– Inhibit virus uncoating by blocking the influenza
encoded M2 protein when inside cells and assembly of
haemagglutinin
• Now rarely used

• Zanamivir and Oseltamivir (Tamiflu)
– Inhibits virus release from infected cells via
inhibition of neuraminidase
Oseltamivir –oral
Zanamivir- inhaled or IV - less likely for resistance to develop

Neuraminidase inhibitors (like Zanamivir and Oseltamivir (Tamiflu)):

• 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
Anti’flu agents - Relenza - (zanamivir) and Tamiflu - (oseltamivir)

22
Q

How can Influenza resistance to anti-virals be seen?/what do we know?

A 
• Resistance sometimes only requires a 
single amino acid change - seen 
recently with swine flu (H1N1) and 
Tamiflu (oseltamivir)
• Point mutation (H275Y; tyrosine 
replacing histidine)
• Seen in immunocompromised 
patients; shed virus for weeks/months
• Likely to be selected from among 
quasispcies during treatment
• Transmissible and virulent
• Remains sensitive to zanamivir;
23
Q

What do we know about the Hepatitis C virus?

A
  • 9.6 Kb RNA virus, enveloped; Flaviviridae family; identified in 1989
  • transmitted via blood – infectious (mother to baby)
  • increasingly common – high risk groups – drug users 20% +ve; – needles (sex?)
  • major cause of chronic liver disease
  • estimated 170 million people infected worldwide
  • occupational risk groups – healthcare workers
  • needle-stick risk – 3% to sero-conversion; chronic carriage almost certain (85%)
  • long incubation – 1 - 6 months
  • vaccination NOT available
  • prevalence in UK - ~6000 per year ( 95% are i/v drug users)
  • early treatment facilitates resolution
24
Q

What does the drug ribavirin (a nucleoside analogue) do?

A

Block RNA synthesis by inhibiting inosine 5’-monophosphate (IMP) dehydrogenase –
this blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate)
and thereby stops GTP synthesis and, consequently, RNA synthesis
Treat: RSV and HepC (in combination with pegylated interferon)

25
Q

What do we know about using Direct-acting antivirals (DAAs) for treating Hepatitis C virus (HCV) ?

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 without IFN or ribavirin.

26
Q

What anti viral drug do we have for covid?

A

Remdesivir:
• prodrug that is metabolized in cells → active nucleotide analog
• active form - inhibits the RNA-dependent RNA polymerase (RdRp)
- Incorporated by the RdRp into the growing RNA chain
- a delayed chain terminator
• Worked for ebola, SARS and MERS
• Clinical efficacy ? - shortens time to recovery in severe COVID-19

Molecular Basis of Disease and Microbiology and Immunology (60 decks)

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