Lecture 20 - HSV and HIV Antiviral Drugs

Question 1

Path of antiviral drug discovery
1)
2)
3)
4)
5)
6)

Answer 1

1) A medical need is identified
2) Relevant mechanism is found through research
3) High-throughput screens of libraries of natural or drug-like products.
4) Successful candidates put through mechanism-based screens.
5) Lead compound selected
6) Drug candidate selected, goes into clinical testing

Question 2

Drugs that block virus attachment
1)
2)

Answer 2

1) Maraviroc, HIV attachment/entry inhibitor

2) T20 (fuzeon), HIV fusion inhibitor

Question 3

Drugs that block uncoating

Answer 3

Amantadine, blocks influenza A M2 ion channel

Question 4

Drugs that block genome synthesis
1)
2)

Answer 4

1) Acyclovir, polymerase inhibitor of herpesviruses

2) Zidovudine, HIV RT inhibitor (NRTI and NNRTI)

Question 5

Drugs that interfere with RNA synthesis

Answer 5

Ribavirin - Nucleoside analogue

Interferon

Question 6

Drugs that interfere with protein synthesis
1)
2)

Answer 6

1) Interferons

2) Saquinivir, Darunavir - HIV protease inhibitors

Question 7

Drugs that interfere with viral release

Answer 7

1) Zanamivir (Relenza)

2) Ostelamivir (Tamiflu) - Both inhibit action of neuraminidase in influenza.

Question 8

Effect of pegylation

Answer 8

Improves bioavailability

Question 9

Effects of IFN-induced proteins

Answer 9

Depending on virus or cell type, these proteins inhibit viral penetration or uncoating, synthesis of mRNA, translation of viral proteins and/or viral assembly or release

Question 10

How are IFN therapies administered?

Answer 10

Injection of purified recombinant proteins

Question 11

What does Amantadine do?

Answer 11

Binds the two diagonally-located alpha-helices of the M2 ion channel in the influenza envelope.
Prevents acidification, fusion of viral envelope with endosome.

Question 12

How is Zanamivir administered?

Answer 12

Inhaled powder

Question 13

How does Zanamivir interfere with influenza NA?

Answer 13

Sialic acid mimetic. Replaces OH group of sialic acid with guanidine, which forms two bonds with the floor of NA binding pocket.

Question 14

How does Ostelamivir interfere with influenza NA?

Answer 14

Sialic acid mimetic. Replaces glycerol with a hydrophobic group, which binds strongly to the wall of the NA binding pocket.

Question 15

Maraviroc

Answer 15

CCR5 coreceptor antagonist. Blocks HIV attachment/entry.

Question 16

HIV viruses that Maraviroc works on

Answer 16

C5 viruses. Doesn’t work against X4 viruses.

Question 17

What do fusion inhibitors act on in HIV?

Answer 17

Prevent gp41 conformational change.

Question 18

CXCR4 coreceptor antagonist

Answer 18

AMD11070 (used to treat X4 HIV)

Question 19

Nucleoside

Answer 19

A nucleotide without any phosphate groups

Question 20

Where on a nucleotide are the phosphate groups?

Answer 20

5’ position of sugar group

Question 21

Substrate for DNA polymerisation

Answer 21

Nucleoside triphosphate

Question 22

Acyclovir

Answer 22

A guanosine analogue.
Has no phosphate groups, lacks 3’ OH required for extension of DNA polymer.
Requires HSV thymidine kinase to attach a phosphate to 5’.

Question 23

Derivatives of acyclovir that have improved bioavailability

Answer 23

Prodrugs. EG: Valacyclovir has a valine attached to 5’ OH group, which is cleaved off within a cell.
The valine assists in the drug passing across the wall of the intestinal tract.

Question 24

Ribavirin
1)
2)
3)
4)
5)

Answer 24

1) A guanosine analogue
2) Inhibit the replication of many DNA and RNA viruses in vitro
3) Shaped like a guanine, but nitrogen base is incomplete.
4) Has 2’, 3’ and 5’ OH group on ribose sugar. Therefore affects RNA polymerisation, not DNA.
5) Unphosphorylated. 5’ phosphorylation occurs within cell.

Question 25

Which form of ribavirin affects viral RNA formation?

Answer 25

Tri-phosphorylated form

Question 26

Ribavirin uses
1)
2)
3)

Answer 26

1) Aerosolised, IV - RSV, influenza
2) Oral or IV - Lassa, ebola
3) Oral - Hepatitis C, in combination with IFN

Question 27

HIV reverse transcriptase inhibitor mechanism
1)
2)
3)

Answer 27

1) Thymidine analogues
2) Phosphorylated by cellular kinase to a tri-phosphorylated form
3) Used by viral RT in preference to normal thymidine, prevents chain elongation

Question 28

Example of a HIV RT inhibitor

Answer 28

Zidovudine (AZT)

Question 29

How does zidovudine differ from thymidine?

Answer 29

3’ OH of thymidine is replaced with N3

Question 30

Nucleoside reverse transcriptase inhibitors
1)
2)
3)

Answer 30

1) Thymidine, cytosine, guanine analogues.
2) Phosphorylated by cellular kinases, used by HIV RT preferentially to normal nucleotides.
3) Prevents chain elongation.

Question 31

Problems with nucleotide RT inhibitors
1)
2)

Answer 31

1) Reduces infection of new cells, but can’t completely eliminate virus
2) Need combination therapy, or resistance emerges

Question 32

Non-nucleotide RT inhibitors

Answer 32

Do not bind to nucleotide binding site of RT
Are not DNA analogues
Directly inhibit RT via other mechanisms

Question 33

HIV protease inhibitor mechanism of action
1)
2)
3)

Answer 33

1) Bind tightly to active site of protease.
2) Peptidomimetics, have a close similarity to target amino acid sequence of protease.
3) Protease can’t break protease inhibitor, can’t cleave gag/pol polyprotein, can’t enzymatically mature HIV virion.

Question 34

Raltegravir
1)
2)

Answer 34

1) An integrase inhibitor (HIV)

2) Blocks integrase strand transfer

Question 35

Example of a protease inhibitor

Answer 35

Lopinavir