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Chemotherapy BMSC2210 > Lecture 2 Hep C & EBOV > Flashcards

Lecture 2 Hep C & EBOV Flashcards

1
Q

What is the definition of a virus?

A

A non-cellular micro-organism that can only replicate within cells

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2
Q

What does it mean by ‘obligate intracellular parasites’?

A

Has to be inside the cell to replicate

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3
Q

Describe the structure of a virus

A

protein coat (capsid) surrounding a nucleic acid genome.

enveloped = surrounded by lipid membrane may have glycoproteins on the membrane to interact with the host cells.

non enveloped = only a protein and genome.

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4
Q

Is the genome made from DNA or RNA?

A

Depends on the virus, can be either

Also can be a single-stranded, duplex, circular or linear

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5
Q

Described the simplified virus life cycle

A

Cell entry → RNA/protein synthesis → genome replication → protein synthesis → assembly of infectious virus particles → released from the cell (cycles back to cell entry)

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6
Q

What does a virus need from the host cells?

A

Raw materials for the synthesis of biomolecules (proteins) e.g. nucleotides, amino acids.

Machinery for the synthesis of biomolecules e.g. protein synthesis requires hosts ribosomes as the virus does not have any.

Enveloped viruses need membranes.

Transport around the cell

Life! - viruses cannot replicate in a dead cell.

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7
Q

What are the ideal characteristics of antiviral drugs?

A

The cell membrane is permeable.

No activity against cellular targets - needs specificity.

Inhibition of virus-encoded protein/virus specific function/process - specificity.

Targets the critical stage of the virus life cycle.

No resistance.

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8
Q

How many people does WHO estimate to be infected with Hep C?

A

73 million

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9
Q

Which is more prevalent, HIV or Hep C?

A

Hep C - 6 million new infections per year

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10
Q

What are the consequences of the Hep C virus?

A

Chronic liver disease

i.e. Fibrosis, cirrhosis, and hepatocellular carcinoma

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11
Q

What is the most common genome group of Hep C?

A

1

Very variable and can mutate easily

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12
Q

What is the most problematic genome group of Hep C in the UK?

A

3

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13
Q

What percentage of people with Hep C go on to have the chronic infection

A

85%

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14
Q

What does the NS3 gene code for? NS = non functional

A

protease and helicases

Therefore cleaving and separating strands of DNA

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15
Q

What does the NS5B gene code for? NS = non functional

A

RNA dependent RNA polymerase - makes RNA copies of the RNA genome

Differs from HIV polymerase as makes RNA not DNA

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16
Q

What does the NS5A gene code for? NS = non functional

A

Not sure as no enzymatic activity but still used as a drug target

17
Q

Explain the Hep C replication cycle

A

The virus binds and enters the cell via endocytosis → uncoating → translation and polyprotein processing/RNA replication → virus budding into intracellular vesicles → transported outside of the cell to fuse to the membrane and release

NOTE: no maturation is required, the virus is already infective

18
Q

Give 2 examples of 1st generation NS3 proteases

A

Telaprevir

Boceprevir

19
Q

Give an example of a 2nd generation NS3 proteases

A

Simeprevir

20
Q

What are the characteristics of 1st generation NS3 proteases?

A

Potent

Prone to resistance

Specific to genotype 1

21
Q

What are the characteristics of 2nd generation NS3 proteases?

A

Potent

Effective against first generation resistance

Effective against some other genotypes but not GT3

22
Q

Name 2 examples of 1st generation NS5A inhibitors

A

Daclatasvir

Ledipasvir

23
Q

How do NS5A inhibitors work?

A

Predicted to target specifically domain I protein of NS5A which has roles in:

  • Virus RNA replication (with domain 2)
  • Virus assembly (with domain 3)
  • Binding to viral RNA (all domains)
  • Binding multiple cellular factors
24
Q

How potent are NS5A inhibitors?

A

HIGHLY! very low dose of drug needed

25
Q

Name an example of 2nd generation NS5A inhibitor

A

velpatasvir

Pan genotypic - drugs that work against every genotype

26
Q

Name an example of a NS5B inhibitor and how it works

A

Sofosbuvir

RNA polymerase production is inhibited

27
Q

What is the guideline treatment for Hep C genotypes 1-12 via NICE recommendations?

A

Sofosbuvir (NS5B) + Velapatasvir (NS5A)

28
Q

What is the guideline treatment for Hep C genotypes 1-12 via FDA recommendations?

A

Sofosbuvir (NS5B) + Velapatasvir (NS5A) + Voxilaprevir (NS3)

29
Q

What is around the total cost of Hep C treatment for 12 weeks?

A

£40,000

30
Q

What is the Ebola virus (EBOV)?

A

Ebola hemorrhagic fever.

a severe and often fatal illness in humans.

Fatality 25-90%

BSL4 pathogen.

Virion is filamentous ~970nm long, 80 nm diameter.

31
Q

What is the treatment for the Ebola virus?

A

No antiviral treatment is available.

2 potential vaccines used experimentally e.g. ‘ring vaccination’ in response to the outbreak.

2 potential vaccines are undergoing human safety testing BUT Biological Safety Level (BSL4) containment hinders the development of inhibitors.

32
Q

When was Ebola first identified?

A

EVD first identified in 1976 with 2 outbreaks.

1 in South Sudan and 1 in DRC.

In DRC the outbreak occurred near the Ebola River - which the genus takes its name.

33
Q

How many proteins does the Ebola virus make?

A

EBOV makes 7 proteins

BUT only 4 proteins are needed for EBOV genome replication:

1) NP
2) VP35
3) VP30
4) L

34
Q

What interactions are essential for EBOV replication.

A
  1. During RNA synthesis, EBOV nucleoprotein alternates between an RNA template bound form and a template-free form to allow the polymerase access to the RNA.
  2. VP35 binds to the N-protein and releases the complexed RNA (IN VITRO)
  3. THIS INTERACTION IS ESSENTIAL FOR EBOV REPLICATION
  4. Using the crystal structure of the nucleoprotein (NP), a hydrophobic pocket was identified.
  5. This pocket established as a target for structure-based design of small molecule inhibitors (SMIs) of EBOV replication. Leung et al (2015) & Dong et al (2015)
35
Q

What was the in silico drug design for EVOB?

A

In silico drug design: NP/VP35 interaction

Dong et al. (2015) aimed to identify or design compounds that bind to NP and compete with VP35 thereby blocking EBOV genome replication.

Using the crystal structure of the NP, a hydrophobic pocket was identified. Therefore, this pocket was investigated as a target for structure-based design of small molecule inhibitors (SMIs) of EBOV replication.

36
Q

What were the candidate EBOV antiviral drugs in Easton et al. (2018)

A
  • MCCB4
  • Predicted to bind to hotspots 1 & 2
  • The EC50 was 4.8 micromoles
  • Low activity (> 100 mM) against controls
  • Cytotoxicity 50% (CC50) > 100 micromoles
  • Selectivity index > 20.8

Chemotherapy BMSC2210 (14 decks)

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