Lec 17: Anti-viral Drugs

Question 1

For a long time there were very few…

This was because…

Answer 1

…anti-viral drugs comparing with anti-bacterial and anti-fungal drugs.
…it was difficult to find compounds that interfere specifically with viral activities without causing significant harm to host cell activities.

Question 2

main potential drug target

Answer 2

many virus specific activities

Question 3

if the virus produces enzymes…

Answer 3

DNA replication provides a target

ex: DNA polymerase, thymidine kinase) distinct from those of the host

Question 4

• Screening compounds for…
• Testing dilutions of…
• Evidence of interferes with…

Answer 4

…anti-viral activity
…the compounds against a range of viruses growing in cell cultures
…the replication of a virus: inhibition of cytopathic effect (CPE) or inhibition of plaque formation.

Question 5

“IC50” =

Answer 5

For each potentially useful compound, the concentration that inhibits CPE or plaque formation by 50 per cent is determined — 50 per cent inhibitory concentration (IC50).

Question 6

Now the screening compounds for anti-viral activity has been…

Answer 6

largely replaced by the rational design of drugs.

Question 7

To stop DNA chain extension, use

Answer 7

analogs

Question 8

Development of anti-viral drugs: (6 Steps IN ORDER)

Answer 8

1. ) Decide upon a target activity for the drug
2. ) Choose a target protein
3. ) Resolve the structure of the target protein
4. ) Select a target site on the protein
5. ) Computer program assisted design of compounds that will bind the site
6. ) Safety test

Question 9

Safety test =

Answer 9

Determine the ratio of the compound’s cell toxicity to its antiviral activity. This ratio is known as the selectivity index (SI) and is expressed by the formula

Question 10

(GOOD) SI equation:

Answer 10

(HIGH) SI = (min conc inhibiting cell proliferation (or DNA synth)) (HIGH) / (min conc inhibiting virus replication) (LOW)

Question 11

Good potential drug =

Answer 11

LOW IC50 and a HIGH SI.

Question 12

HIV Drug Examples: (3)

Answer 12

1. ) Inhibitors of reverse transcription (Nevirapine)
2. ) HIV protease inhibitors
3. ) HIV fusion inhibitors

Question 13

(HIV protease inhibitors)

The maturation of a retrovirus virion involves…

Answer 13

…the cleavage by a virus protease of the Gag and Gag–Pol proteins to form the virion proteins—-Peptide mimics of the cleavage site

Question 14

(HIV fusion inhibitors)

gp41 must undergo…

Answer 14

…a conformational change to enable the membrane fusion—-drugs bind to gp41 and inhibiting the conformational change

Question 15

Drug Resistance is a result of

Answer 15

natural selection

Question 16

(Drug Resistance)

Viruses, especially ___ viruses, can

Answer 16

RNA

mutate at high frequencies and evolve rapidly—- genotypes encoding drug resistance can arise rapidly.

Question 17

(Drug Resistance)

A measure of the degree of resistance can be obtained by

Answer 17

determining the IC50.

Question 18

(Drug Resistance)
A virus strain is considered to be ‘resistant’ to a drug if…
Reason =

Answer 18

…it is able to replicate in the body in the presence of a concentration of the drug that inhibits replication of ‘sensitive’ strains.
= one or more mutations in the genes encoding the proteins that are the drug targets.

Question 19

Problems with the use of anti viral drugs: (3)

Answer 19

1. ) Drug-resistance (no time to make profit)
2. ) Mostly do not eliminate virus infections from the body (only suppress to certain point)
3. ) Side-effects

Question 20

Goals of anti-viral drug research: (2)

Answer 20

1. ) Reduce the severity of the problems discussed in previous slide
2. ) Develop drugs for virus diseases that are currently untreatable