Topic 6C antimicrobial (antiviral)

Question 1

What is antiviral

Answer 1

more difficult to design selectively toxic agents since viruses rely mostly on host cellular machinery

Question 2

What is inhibition of viral entry

Answer 2

• viruses must enter a host cell and use the host’s cellular machinery to replicate.

Question 3

What is enfuvirtide

Answer 3

attaches to the gp41 spike protein of HIV, blocking contact with human CD4 and CXCR4.

Question 4

What is miravoc

Answer 4

c - attaches to human CCR5, blocking contact with the HIV gp120 spike protein.

Question 5

What is palivizumab

Answer 5

a monoclonal antibody which binds to the fusion protein of respiratory syncytial virus (RSV), preventing binding to the human epithelial cell receptor

Question 6

What is inhibition of viral uncoating

Answer 6

viruses must release their proteins and DNA/RNA from the capsid to replicate.

Question 7

What is amantadine

Answer 7

plugs the M2 ion pore of influenza Type A, preventing the uncoating process from completing.
Widespread usage of amantadine has lead to resistance

Question 8

What is rimantidine

Answer 8

• similar mechanism of action to amantadine, but better tolerated (less side effects).

Question 9

What is inhibition of viral nucleic acid synthesis

Answer 9

most antivirals fall into this category as this is where viruses differ the most from humans.
Viral genome replication relies on one or more of: cellular DNA polymerase, cellular RNA polymerase,
viral RNA-dependent RNA polymerase, or viral RNA-dependent DNA polymerase (aka reverse transcriptase).
Most of these medications use nucleoside analogs created by substituting atoms or functional groups.

Question 10

What is DNA nucleoside analog

Answer 10

nucleoside analogs which are added to the chain, but prevent further additions.

Question 11

What is acyclovir

Answer 11

• a guanosine analog which strongly interacts with the thymidine kinase of the herpesviridae, which metabolizes it into acyclovir triphosphate. This metabolite acts as a normal guanosine, but the lack of a 3’ -OH group prevents further additions, terminating the chain.
  Acyclovir only weakly interacts with the human thymidine kinase, so it only affects virally infected cells.
  Derivatives include: valacyclovir for herpes genitalis (HSV-2) & herpes zoster (shingles), penciclovir/famciclovir for
  herpes labialis (HSV-1 aka “cold sores”) and ganciclovir for cytomegalovirus (CMV).

Question 12

What are other nucleoside analogs

Answer 12

• cidofovir (cytosine analog), vidarabine (adenosine analog), idoxuridine (thymidine analog),
  and trifluridine (thymidine analog). These all interact with the human kinase, limiting their usefulness

Question 13

What are DNA phrophosphate analogs

Answer 13

nucleoside analogs which can not be added to the chain.

Question 14

What is foscarnet

Answer 14

a pyrophosphate analog which inhibits nucleotide addition to the chain by preventing dNTP hydrolysis and release of pyrophosphate from the viral DNA polymerase.
Foscarnet is effective against herpes simplex virus 1 (HSV-1) and varicella zoster virus (VZV).

Question 15

What is reverse transcriptase inhibitors

Answer 15

• all are effective against HIV, some are also effective against HBV

Question 16

What is nucleoside reverse transcription inhibitors

Answer 16

these are metabolized to a nucleoside analog (for example zidovudine is a structural analog of thymidine), but the lack of a 3’ -OH group prevents further additions, terminating the chain. They are selective for reverse transcriptase which is not found in human cells.
All of the NRTIs are effective against HIV. Only lamivudine (cytosine analog), emtricitabine (cytosine analog), and tenofovir (adenosine analog) are effective against the hepatitis B virus (HBV).

Question 17

What is Non-Nucleoside Reverse Transcription Inhibitors (NNRTIs)

Answer 17

• bind to reverse transcriptase and alters its molecular conformation, preventing it from binding to nucleosides.
  Includes: nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine. They are all effective against HIV, but must be used as part of combination therapy as individual use triggers rapid mutation.

Question 18

What is inhibitors of related virally encoded enzymes

Answer 18

bind to enzymes not encoded by host cell.

Question 19

What is sofosbuvir

Answer 19

metabolized to a structural analog of uridine, but causes steric hindrance which terminates the RNA chain.
Sofosbuvir is very effective at curing hepatitis C virus (HCV), but it is extremely expensive!

Question 20

What is ribavirin

Answer 20

• prevents synthesis of guanine by replacing a metabolic precursor.
  Ribavirin is usually used against respiratory syncytial virus (RSV) in a mist formulation.

Question 21

What is raltegravir

Answer 21

• prevents integrase from adding proviral DNA into host cell chromosome. Effective against HIV.

Question 22

What is inhibition of viral protein synthesis

Answer 22

inhibition of protein synthetic machinery in virally infected cells.

Question 23

What is alpha interferon

Answer 23

binds to cellular receptors to trigger production of antiviral proteins: 2,5-oligo A synthetase, 2,5-oligo A-
dependent ribonuclease, and eIF-2 kinase.
When 2,5-oligo A synthetase binds to viral dsRNA, 2,5-oligo A-dependent ribonuclease is activated to degrade it. Viral dsRNA activates eIF-2 kinase which phosphorylates (deactivates) eIF-2, preventing initiation of translation.

Question 24

What is fomivirsen

Answer 24

an antisense DNA that is complementary to the mRNA of cytomegalovirus (CMV). This DNA-mRNA complex can not be bound by human ribosomes, preventing translation. This is the only antisense DNA medication!

Question 25

What is inhibition of viral proteases

Answer 25

viruses with non-segmented genomes frequently produce long “pre-proteins” requiring protease cleavage into their active forms. Inhibition is achieved by drugs that possess peptide bonds in non-cleavable conformations.

Question 26

What is protease inhibitors against HIV

Answer 26

• saquinavir, lopinavir, ritonavir, indinavir, amprenavir, darunavir, nelfinavir. These drugs must be used in combination with other medications to prevent resistance.
  Protease inhibitors against HCV - boceprevir, simeprevir, telaprevir.

Question 27

What is inhibition of viral neuraminidases (viral release)

Answer 27

enveloped viruses can only be released by budding, in which their matrix protein steals part of the host cell’s plasma membrane. Completion of the budding process requires the neuraminidase enzyme which cleaves neuraminic acid, the final attachment point

Question 28

What is oseltamivir & Zanamivir

Answer 28

neuraminidase inhibitors which are effective against the influenza virus. They must be used in the early stages of the viral infection to have any effect!