Antivirals Flashcards
Describe the structure of viruses.
• Viruses are small infective agents consisting essentially of nucleic acid (RNA or DNA) enclosed in a protein coat (capsomeres). Can potentially be enveloped.
What does it mean when we say that viruses are obligate intracellular parasites ?
They have to use the metabolic processes of the host cell (since they have no metabolic machinery of their own), which they enter and infect.
Where do some viruses derive their envelope form ?
They pinch some of the plasma membrane of our cells.
Is taxonomy important for viruses ? Why or why not ?
Yes it is, because it dictates treatment (some forms of treatment will work against some types of viruses but not others)
Explain the process of viral replication.
-Basically: Attach to and enter a living host cell-animal, plant or bacterial-and use its metabolic processes.
- The binding sites on the virus are polypeptides on the envelope or capsid. These are receptors which are normal membrane constituents-receptors for cytokines, neurotransmitters or hormones, ion channels, integral membrane glycoproteins, etc.
- Then, with many viruses, the receptor-virus complex enters the cell by receptor-mediated endocytosis during which the virus coat may be removed. Some bypass this route.
- Then, once in the host cell, the nucleic acid of the virus then uses the cell’s machinery for synthesizing nucleic acid and protein and the manufacture of new virus particles.
Identify the main steps in a virus’s life cycle.
- Recognition
- Attachment
- Penetration or Fusion
- Uncoating
- Transcription
- Protein Synthesis
- Replication
- Assembly then lysis and release OR envelopment then budding and release
Identify the main classes of antiviral drugs, explaining which viral process each class interferes with.
- Entry inhibitors: target viral fusion (T20/Enfuvirtide) and a host cell co-receptor (maraviroc)
- Viral uncoating (amantadine/rimantadine)
- Nucleoside anologue chain termination (e.g. Acyclovir, NRTIs)
- NNRTIs (non-nucleoside reverse transcriptase inhibitors) inhibit reverse transcriptase directly (delaviridine, efavirenz)
- Protease inhibitors target the HIV and HCV-encoded protease (Telaprevir and Boceprevir target HCV-encoded protease)
- Integrase Inhibitors (Raltegravir, Elvitegravir and Dolutegravir)
- Virus release inhibitors: influenza NA inhibitors (zanamivir, oseltamivir)
- Immunomodulator PEG-IFN-α
What is immunomodulator PEG-IFN-α used for ?
HCV and HBV treatment
Explain the mechanism of action of protease inhibitors.
- Host mRNAs code directly for functional proteins.
- In HIV, the mRNA is translated into biochemically inert proteins. A virus-specific protease then converts them into various functional proteins.
- Since the protease does not occur in the host, it is a good selective-toxicity target.
Protease inhibitors interfere with the action of those virus-specific proteases
Give examples of DNA viruses.
Herpes Simplex Virus (HSV), Human Papilloma Virus (HPV)
Explain how DNA viruses work.
1) Entry of the viral DNA into the host cell nucleus
2) Transcription of this viral DNA into mRNA by host cell RNA polymerase
3) Translation of the mRNA into virus- specific proteins
What viruses are protease inhibitors used for ?
HCV and HIV
How does aciclovir work to interfere with viral activity/replication ?
Through nucleoside anologue chain termination.
Identify the clinical uses of Aciclovir.
Treatment of herpes simplex virus and varicella zoster virus infections (especially indicated in compromised patients). This includes:
-Genital herpes simplex (treatment and prevention)
-Herpes simplex labialis (cold sores)
-Shingles
-Acute chickenpox in immunocompromised patients
-Herpes simplex encephalitis
-Acute mucocutaneous HSV infections in immunocompromised patients
-Herpes of the eye and herpes simplex blepharitis (a chronic (long-term) form of
herpes eye infection)
-Prevention of herpes viruses in immunocompromised people (such as people undergoing cancer chemotherapy)
Give examples of RNA viruses.
Influenza (Flu), Hepatitis C Virus (HCV)
How are RNA viruses classified ? List the different classes.
RNA viruses classified according to the sense or polarity of their RNA
• Positive-sense viral RNA – is similar to mRNA and can be immediately translated by the host cell.
• Negative-sense viral RNA - is complementary to mRNA and must be converted to positive-sense by an RNA polymerase before translation.
Explain how RNA viruses work.
1) Positive-sense viral RNA immediately translated by the host cell
Negative-sense viral RNA converted to positive-sense by an RNA polymerase then translated
2) RNA polymerase directs the synthesis of more viral genomic RNA
Where does RNA virus and DNA virus replication occur ?
DNA replication - nucleus
RNA replication - cytoplasm
Give examples for Retroviruses.
HIV, Human T cell Leukemia Virus (HTLV)
How do retroviruses work ?
1) The virus contains reverse transcriptase (RT) an RNA- dependent DNA polymerase, which makes a DNA copy of the viral RNA.
2) This DNA copy is integrated into the genome of the host cell and it is then termed a provirus
3) The provirus DNA is transcribed into both new genomic RNA and mRNA for translation into viral proteins using host cell machinery.
What is the relation between retroviruses and cancers ?
An example of retrovirus is Human T cell Leukemia; some RNA retroviruses can transform normal cells into malignant cells.
Why is it difficult to eradicate infection due to a retrovirus ?
Because they are not included in the host genome.
Identify the main mechanistic classes of antiretroviral drugs. How many classes and drugs are there for antiretroviral therapy ?
6 classes of drugs, 25 drugs
Reverse Transcriptase (RT) Inhibitors
1) -Nucleoside analogs: abacavir, didanosine
2) -Non-nucleoside analogs: delaviridine, efavirenz
3) Protease (PR) Inhibitors
Telaprevir and Boceprevir
4) Entry Inhibitors
Maraviroc
5) Fusion Inhibitors
Enfuvirtide
6) Integrase (IN) Inhibitors
Raltegravir
How many NRTIs are approved for use ? How many NNRTIs ?
8 NRTIs
4 NNRTIs
Describe the mechanism of action of NRTIs.
Inhibit viral DNA synthesis by:
- Compete with the natural substrate (dNTPs for DNA synthesis or NTPs for RNA synthesis) in DNA or RNA polymerization, therefore virus specific selectivity
- Act as chain terminators by not offering the 3′-hydroxyl function at the (2′-deoxy)riboside moiety, which is required for attachment of the incoming nucleotide OR nucleotide analogues possessing an hydroxyl function at a position equivalent to the 3′-hydroxyl position act as chain terminator if this hydroxyl group is conformationally constrained and therefore hinders attachment of the incoming nucleotide.
- They are prodrugs and require intracellular phosphorylation by viral and/or cellular kinases to convert them from the 5’-monophosphate form to 5’-triphosphates.
Describe the mechanism of action of NNRTIs.
Binding induces conformational changes that inhibit the catalytic activity of RT
What are NRTIs analogous to ?
Different nucleobases and nucleosides such as guanine, thymidine.
Each NRTI is analogous to a different one.
What is meant by a prodrug ? Give examples of prodrug antivirals.
Biologically inactive compound which can be metabolized in the body to produce a drug.
NRTIs
How do integrases work in the HIV virus ?
HIV integrase mediates two critical reactions; firstly 3’ end processing of the double-stranded viral DNA ends and then strand transfer which joins the viral DNA to the host chromosomal DNA forming a functionally integrated provirus.
How do integrase inhibitors function ?
Interfere with the two critical reactions performed by HIV integrase: firstly 3’ end processing of the double-stranded viral DNA ends and then strand transfer which joins the viral DNA to the host chromosomal DNA forming a functionally integrated provirus.
Therefore inhibits integration of transcribed DNA into host genome.
Which virus primarily uses the process of fusion ?
HIV virus
Explain the process of fusion with the HIV virus.
Entry of HIV into a new cell is mediated by the Env glycoprotein spike (a trimer of gp120 and gp41). Entry requires the receptor CD4 plus one of two co-receptors, CCR5 or CXCR4.
What virus primarily uses the process of integration ?
HIV virus
How do fusion inhibitors work ?
Enfuvirtide/T20 binds to gp41 and interferes with its ability to approximate the two membranes.
How do entry inhibitors work ?
1) Fusion inhibitors
2) Maraviroc (“chemokine receptor antagonist/CCR5 inhibitor”) binds to CCR5, preventing an interaction with gp120.
Define HAART.
Highly Active Antiretroviral Therapy
Combinations of 3-4 different drugs aiming to reduce viral load and prevent resistance.
Most commonly two NRTIs in combination With an NNRTI, PI or most recently an integrase inhibitor
What is atripla ?
A pill which combines of 2 NRTIs and 1 NNRTI
What is the low cost generic fixed dose combination being explored for the developing world ?
2 NRTIs and 1 NNRTI
Give an example of drug which combines both 2 NRTIs and 1 NNRTI.
Atripla
What is the point of alternative third agents in HAART (in addition to the two NRTIs) ?
Must be different alternatives to account for resistance + adverse effects
Explain the mechanism of action of viral uncoating inhibitors. Identify viral uncoating inhibitors.
• At two stages of viral replication within the host cell, a viral membrane protein, M2, functions as an ion channel, (especially useful for viral uncoating). The stages are (i) the fusion of viral membrane and endosome membrane and (ii) the later stage of assembly and release of new virions at the host cell surface.
Viral uncoating inhibitors block this ion channel (i.e. M2 Ion Channel Inhibitors)
• They are concentrated in lysosomes, and block the influx of H+ ions (increase the pH in the compartment), thereby inhibiting uncoating and release of free ribonucleioproteins into the cytoplasm). They therefore interfere with the fusion of lysosomes and endocytosed viral-containing vesicles.
E.g. Amantadine and Rimantadine
Identify influenza inhibitors.
- Viral uncoating inhibitors (Amantadine/Rimantadine)
- Neuraminidase (NA) Inhibitors (Oseltamivir = Tamiflu and Zanamivir = Relenza)
- Baloxavir
What virus is neuraminidase associated with ? Explain the mechanism of action of neuraminidase.
Influenza NA (neuraminidase) functions in Influenza infection by cleaving sialic acid from the cell surface so that newly made viruses are released and able to spread to uninfected cells.
Explain the mechanism of action of neuraminidase inhibitors.
NA inhibitors mimic the sialic acid natural substrate by binding to the NA active site, preventing NA function and hence halting virus replication.
Explain the main problem of NA inhibitors.
By the time you know the patient has the flu, there isn’t much of a point in stopping the virus spreading because it has already spread.
What virus is Baloxavir used against ? Explain its mechanism of action.
Influenza
Inhibits mRNA replication and prevents transcription and new virus formation
How effective are each of the classes of anti-flu drugs ?
NA inhibitors (Tamiflu, Relenza) - Ineffective because by the time you know you have the flu it’s too late to stop the spread of the virus
Baloxavir - shorten time for symptom resolution but unclear if prevent severe
complications of flu
Uncoating inhibitors- shorten time for symptom resolution but unclear if prevent severe complications of flu
Identify the main drugs used for treatment of Hep C.
- Ribavirin
- Peginterferon alpha
- Protease inhibitors (grazoprevir, glecaprevir)
(Interferon-free treatment consisting of PI + ribavarin gives best response)
Define genotype in the context of Hep C.
Hep C treatment is different depending on genotype of the organism.
Genotype 3 more difficult to treat (and longer).
Identify other viruses for which treatment is evolving.
Hep B and Enteroviruses
Identify HCV Protease Inhibitors (PIs).
Telaprevir and Boceprevir
What is the problem with oral aciclovir ?
Oral acyclovir does not decrease the risk of pain.
Identify the main herpes virus drugs and identify the virus they target.
- Acyclovir and Valaciclovir for herpes simplex virus and varicella zoster virus (Valaciclovir is a prodrug with better oral availability + indication for acyclovir is in compromised patients)
- Ganciclovir and valganciclovir for CMV
Give examples of protease inhibitors. Which virus are these used against ?
Telaprevir and Boceprevir
Against HCV
Give examples of integrase inhibitors. Which virus are these used against ?
Raltegravir, Elvitegravir, and Dolutegravir For HIV (Raltegravir for patients with HIV resistant to HAART)
What kind of molecule is T20/Enfuvirtide ? How is it administered ?
Synthetic peptide
Requires subcutaneous injection
Which antiviral drug requires genotype testing ?
Maraviroc
What is the main difference between HIV treatment in the Western world, and developing countries ?
In poorer countries, given at fixed drugs (because lower cost) so less opportunity to deal with resistance and adverse events
How is each of the main Neuraminidase inhibitors administered ? How were they developed ?
- Zanamivir = Relenza (nasal spray)
- Oseltamivir = Tamiflu (oral)
Both developed by a structure-based design strategy
