Viral Drugs (general)

Question 1

In general why is viral drug design so much harder than bacterial drug design?

Answer 1

• There are very few targets because they use out cells and out machinery to replicate
• Viruses are also a more heterogenous group than bacteria so medications can’t usually be generalized across types
• Our targets are within the viral cycle, problem is that by the time the disease is symptomatic many viral cycles have likely occured already

Question 2

What is the primary target used in antiviral drugs?

Answer 2

• Virally encoded proteins

- Some host proteins that we rarely use but that Viruses often use

Question 3

How do we prevent emergence of resistance in anti-viral Drugs?

Answer 3

• Using Two or more drugs that target a single stage (e.g. two or more inhibitors of reverse transcription)
• Targeting more than one stage in the HIV life-cycle

Question 4

What Flu drugs act as Ion Channel Blockers?

Answer 4

• Atmantadine

- Rimantidine

Question 5

What are the only two targets in the cell cycle for Flu Drugs?

Answer 5

1. Ion Channel Blockers (prevents uncoating)

2. Neuraminidase Inhibitors (prevents release of progeny)

Question 6

What Flu Drugs act as Neuraminidase Inhibitors?

Answer 6

1. Zanamivir

2. Oseltamivir

Question 7

What two HIV drugs work to prevent HIV entry into the host cell?
- how do their MOAs differ?

Answer 7

1. Maraviroc - small molecule antagonist of CCR5
2. Enfuvirtide (T-20) binds to HR1 and prevents the HR2-HR1 interaction

***They prevent the virus from ever binding to the host

Question 8

What general process do amantadine and rimantadine work to block?

Answer 8

• In general they are M2 ion channel blockers
  1) Hemagglutinin binds endosome and virus envelope together on acidification from endosome ATP proton pumps
  2) M2 proton pumps in the flu membrane must also open to induce RNP release from the fused Virus:Endosome

Question 9

What infection types are treated mostly with nucleoside analogues?

Answer 9

• Herpes and HIV infections

Question 10

T or F: all nucleoside analogues require metabolic activation.

Answer 10

True, they are usually activated to the Triphosphate Form

Question 11

Why are inhibitors of Nucleic Acid Synthesis excellent drug targets?

Answer 11

• Viruses rely on polymerases for genomic replication, these must be dissimilar enough from mammalian nucleotides to avoid inhibition of mammalian processes

Question 12

What is believed to be the root cause of most of the adverse affects of NRTIs used to treat HIV?

Answer 12

Mitochondrial Polymerase is also inhibited leading to adverse affects

Question 13

What are the NRTIs (nucleoside reverse transcriptase inhibitor) used to treat HIV?

Answer 13

• ABACAVIR
• LAMIVUDINE (3-TC)
• TENOFOVIR DISOPROXIL
• ZIDOVUDINE (AZT)
• EMTRICITABINE
• didanosine (ddl)
• Stavudine

Question 14

How is resistance often conferred against NRTIs?

Answer 14

• Cross-resistance to NRTIs is associated with mutations at at a bunch of different Reverse Transcriptase codons

Question 15

How do NNRTIs differ from NTRIs?

Answer 15

• NTRIs bind in the active site, NNRTIs bind to a hydrophobic binding pocket on the p66 protein of HIV-1 transcriptase, far from the binding pocket.
• These drugs DO NOT NEED phosphorylation to attain activity

Question 16

What are the 2 NNRTIs (non-nucleoside Reverse Transcriptase Inhibitors)?

Answer 16

EFAVIRENZ

NEVIRAPINE

Question 17

What is a major source of variability in metabolism of HIV-1 protease inhibitors?

Answer 17

Some like RITONAVIR are INHIBIT CYP3A4 while others like ATAZANVIR have no effect

Question 18

How does resistance to RALTEGRAVIR arise?

- what does RALEGRAVIR do?

Answer 18

• Mutations in the integrase protein can cause Ralegravir to become ineffective
• Ralegravir inhibits HIV 1/2 integrase to prevent HIV DNA from getting inserted into Human DNA

Question 19

What drugs are HIV-1 Protease inhibitors?

Answer 19

• ATAZANAVIR
• RITONAVIR
• amprenavir
• indinavir
• lopinavir
• nelfinavir
• saquinavir

Question 20

What do HIV-1 Protease inhibitors do?

Answer 20

They block the HIV virus’ aspartyl protease enzyme that is needed to cleave HIV gag and pol precursor polypeptides, as well as Reverse Transcriptase, and Integrase into active polypeptides

Question 21

How does resistance against HIV-1 protease inhibitors arise?

Answer 21

• Resitence arises at the active site, then may occur at secondary sites later

Question 22

What are the protease inhibitors for the HCV virus?

- what exactly are they inhibiting?

Answer 22

• Block NS3/4A Serine Protease from cleaving HCV polypeptides into functional proteins

Question 23

What problems with resistance are seen with the HCV protease inhibitors?

Answer 23

• Rapid Resistance because the HCV virus mutates so rapidly

Question 24

What are the HCV protease inhibitors?

Answer 24

• BOCEPREVIR

- TELAPREVIR

Question 25

What drug acts to mimic the effects of INF-alpha?

- what are these effects?

Answer 25

PEGINTERFERON

• Activates Mx protein that inhibits production of mRNA
• inhibits Translation of proteins
• Inhibits Post Translational Processing (PTP)

Question 26

What drugs act as neuraminidase inhibitors?

Answer 26

• Zanamivir

- Oseltamivir

Question 27

How do Zanamivir and Oseltamivir work?

Answer 27

• They are selective sialic acid analogue inhibitors that produce conformational change in the neuraminidase of influenza A and B.

**Prevents Progeny from Exiting the Cell

Question 28

What are the underlying principles of HIV chemotherapy?

Answer 28

• All aspects of HIV are derived from viral effects on CD4+ T cells
• Long term suppression of HIV and replenishment of CD4+ cells is beneficial
• Actively replicating HIV must be present for this to be effective (treatment WILL NOT ERRADICATE QUIESCENT HIV cells)
• Some infected T-cells will survive for decades
• Drug therapy DOES NOT CAUSE mutations but may apply a selective pressure for them

Question 29

How do you administer Combination HIV chemotherapy?

Answer 29

• Give 3 drugs simultaneously (4 or more may be used in pretreated patients with resistant virus)

Question 30

What do increases in viral RNA levels despite continued adherence to HIV chemotherapy drug regimens suggest?
- what do we do in this case ?

Answer 30

VIRAL RESISTANCE

• We must change the regimen (often we must change all drugs)
• some resistant strains will remain in T-lymphocytes indefinitely

Question 31

What usually causes treatment failure in HIV Chemotherapy?

- how do we attenuate this?

Answer 31

Non-adherance, we can prescribe drugs with longer half-lives to be more forgiving of missed doses

Question 32

What are the preferred agents of HBV Chemotherapy?

Answer 32

Tenofovir Disoproxil fumarate
Entecavir

(Others: telbivudine, adefovir dipivoxil, Lamivudine, and Emtricitabine)

Question 33

What drugs would you give for HCV genotype 1 Chemotherapy?

Answer 33

Peginterferon-alpha + Ribavirin + Telaprevir or Boceprevir HCV NS3/4A protease inhibitors

Question 34

What drugs would you give for HCE genotype 2 and 3 chemotherapy?

Answer 34

Peginterferon-alpha + Ribavirin

Question 35

What drugs are typically administered for Anti-Flu chemostherapy?

Answer 35

Oseltamivir