Lecture 2 Hep C & EBOV Flashcards
What is the definition of a virus?
A non-cellular micro-organism that can only replicate within cells
What does it mean by ‘obligate intracellular parasites’?
Has to be inside the cell to replicate
Describe the structure of a virus
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.
Is the genome made from DNA or RNA?
Depends on the virus, can be either
Also can be a single-stranded, duplex, circular or linear
Described the simplified virus life cycle
Cell entry → RNA/protein synthesis → genome replication → protein synthesis → assembly of infectious virus particles → released from the cell (cycles back to cell entry)
What does a virus need from the host cells?
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.
What are the ideal characteristics of antiviral drugs?
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.
How many people does WHO estimate to be infected with Hep C?
73 million
Which is more prevalent, HIV or Hep C?
Hep C - 6 million new infections per year
What are the consequences of the Hep C virus?
Chronic liver disease
i.e. Fibrosis, cirrhosis, and hepatocellular carcinoma
What is the most common genome group of Hep C?
1
Very variable and can mutate easily
What is the most problematic genome group of Hep C in the UK?
3
What percentage of people with Hep C go on to have the chronic infection
85%
What does the NS3 gene code for? NS = non functional
protease and helicases
Therefore cleaving and separating strands of DNA
What does the NS5B gene code for? NS = non functional
RNA dependent RNA polymerase - makes RNA copies of the RNA genome
Differs from HIV polymerase as makes RNA not DNA
What does the NS5A gene code for? NS = non functional
Not sure as no enzymatic activity but still used as a drug target
Explain the Hep C replication cycle
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
Give 2 examples of 1st generation NS3 proteases
Telaprevir
Boceprevir
Give an example of a 2nd generation NS3 proteases
Simeprevir
What are the characteristics of 1st generation NS3 proteases?
Potent
Prone to resistance
Specific to genotype 1
What are the characteristics of 2nd generation NS3 proteases?
Potent
Effective against first generation resistance
Effective against some other genotypes but not GT3
Name 2 examples of 1st generation NS5A inhibitors
Daclatasvir
Ledipasvir
How do NS5A inhibitors work?
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
How potent are NS5A inhibitors?
HIGHLY! very low dose of drug needed
