Lecture 14 - Antivirals Flashcards Preview

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Flashcards in Lecture 14 - Antivirals Deck (52)
1

Describe the background of virus biology

-Obligate intracellular parasites
-No cell wall or plasmamembrane
-No metabolism - so tough to target
-Few drugs block reproduction selectively
-Pharmacology focused on late symptoms
-Few virus groups can be effectively treated with drugs

2

Describe cytopathic effects of virus

-Host cell metabolism hijacked
-Viral-induced suppression of host homeostasis
-Viral proteins induce lysis or apoptosis
-Viral proteins trigger host immune response
-Inflammatory rxn kills host
-All above involve lytic cycle - generation of new virus
-Virus can become latent - host cell survives
-No overt immune response

3

Describe virus groups that are available for treatment

-Herpes/Varicella zoster/Cytomegalovirus (CMV)
-HIV-1 and HIV-2
-Respiratory infection - influenza A/B
-Hepatic - hepatitis A-E (B and C most common - HBV and HCV)

4

Describe Herpes simplex virus (HSV)

-Neurotropic
-Complex dsDNA viruses - at least 8 members
-HSV-1 (cold sores), HSV - 2 (genital herpes)
-Chicken pox (Varicella zoster - VZV), shingles, cytomegalovirus (CMV)
-Close contact transmission
-Latent infection

5

Describe HSV - life cycle

-Lytic cycle in epithelial cells; 80 genes in cascade
-Viral progeny spread to sensory neurons
-Retrogradely transported to cell body
-Latent - circular episcopal DNA (nucleosome)
-No immune signature
-No cytotoxic effect
-Stress-related reactivation
-Anterograde transport
-Shingles - Varicella zoster rash and pain (neuralgia)

6

Describe HSV - replication

-Viral DNA enters nucleus and circularizes
-Immediate early genes - use host RNA pol (2-4 hour post infection)
-Host transcription factors
-VP16 viral activator
-Binds host cell factor that activates OCT1 (host)
-IEG trigger early genes
-E proteins control viral DNA replication
-DNA replication initiates alte genes - viral structure and assembly

7

Describe HSV - acyclovir (Zovirax)

-Synthetic nucleoside analog
-Viral thymidine kinase converts to acyclovir-GMP
-Acyclo-GTP inhibitor of viral DNA polymerase (x100 over host)
-Viral DNA chain termination
-Treatment for genital herpes, shingles, cold sores and chicken pox
-Oral or intravenous

8

Other HSV drugs include?

Famciclovir: a prodrug of 6-deoxypenciclovir - 1st pass metabolism convert to penciclovir. Active against HSV-1, HSV-2 and VZC. Oral or topical

Penciclovir: guanosine analogue; topical formulation

Docasonal: inhibitor of fusion of HSV-1 virus with host cell. Topical formulation.

9

Describe CMV

-CMV a major problem in immune-compromised patients (organ transplantation)
-Can lead to liver failure, colitis and retinitis (inflammation of retina)

10

Describe the drugs to treat CMV

Ganciclovir: analog of acyclovir; x20-100 more effective against CMV; targets virus specific protein kinase phosphor-transferase UL97. Intravenous

Valganciclovir: prodrug of ganciclovir. Oral administration

Foscarnet: reversible inhibitor of viral DNA/RNA polymerases; CMV infection and resistant HSV; range of side effects (intravenous only)

11

Describe Human Immunodeficiency Virus (HIV) facts

-Lentivirus (HIV-1 and HIV-2)
-Retrovirus family - +ssRNA virus
-Fast replication cycle and multiple infection
-Reverse transcriptase - error prone - drug resistance
-Latent ability (hides out in cells, gets expressed later) - viral integrase enzyme
-Acquired immune deficiency (AIDs)
-Blood/fluid transfer
-Pandemic
-25 million killed
-0.6% infected

12

Describe how HIV works

-Invades helper T cells (CD4 +)
-Also macrophages and dendritic cells
-Targets CD4 receptors and chemokine co-receptors (CCR5 and CCR4)
-Loss of CD4+ cells
-Cell-mediated immunity lost
-90% progress to AIDs within 10-15 years
-Drug therapy raised survival 3 to 5-fold

13

Origin of HIV:
"USA first" model
Probability = ?

0.01%

14

Origin of HIV:
"Haiti first" model
Probability = ?

99.8%

15

Treatment options for HIV

-No cure
-Post-exposure prophylaxis
-Highly active anti-retroviral therapy (HAART)
-3 drugs belonging to at least 2 classes
-Newer integrase and entry inhibitors can now be added
-Aggressive treatment in children

16

NRTI

Nucleoside/nucleotide reverse transcriptase inhibitors

17

Describe NRTIs

-Analogs of native ribosomes - lack 3' hydroxyl
-Phosphorylated to triphosphate by host enzymes
-Incorporated in viral DNA
-Lack of 3'-hydroxyl leads to DNA chain termination
-Drug affinity > HIV reverse transcriptase
-Toxicity due to inhibition of mitochondrial (mt) DNA polymerase

18

Describe the NRTI - Zidovudine (AZT)

-First drug approved
-FDA-approved March 20th 1987
-Twice daily 300 mg as part of HAART
-GSK patent expired 2005
-Pyrimidine analog
-Converted to triphosphate by cellular enzymes
-Oral delivery; good penetration across BBB
-T1/2 3 hour
-Toxic to bone marrow (mitochondria do not have full copies of their own DNA - leads to many problems and damage of cells, specifically bone marrow)
-Inhibits DNA pol-gamma in mitochondria

19

Describe the NRTI - Abacavir

-guanosine analogue
-unaffected by food
-t1/2 = 1.5 hours
-not to be taken with alcohol
-resistance develops slowly
-hypersensitivity reactions can be severe
-higher risk of myocardial infarction

20

Describe the NRTI - Lamivudine

-cytosine analogue
-good bioavailability
-unaffected by food
-t1/2 = 2.5 hours
-recommended in pregnant women
-inhibits RT in HIV and HBV
-does not inhibit mtDNA or bone marrow

21

Describe the NRTI - Emtricitabine

-fluor-derivative of lamivudine
-inhibits RT in HIV and HBV
-long intracellular half-life of 39 hour makes once a day treatment feasible
-good bioavailability and unaffected by food
-oral formulation contraindicated in young children, pregnant women and renal hepatic failure

22

Describe the NRTI - Tenofovir

-acyclic analogue of adenosine
-long half-life allows once a day dosing
-GI complaints and renal dysfunction contraindicated

23

NNRTI

Non-Nucleoside/nucleotide reverse transcriptase inhibitors

24

Describe NNRTIs

-non-competitive inhibitors of HIV-1 reverse transcriptase
-no activation required
-no effect on bone marrow or mitochondrial DNA polymerase

25

Describe the NNRTI - Efavirenz

-once daily treatment on an empty stomach
-metabolized by CYP3A4 and CYP2B6.
-CNS side effects
-Some severe (ex. psychosis, skin rash, avoid in pregnant women, induces CYP3A4)

26

Describe the NNRTI - Nevirapine

-good oral bioavailability
-not food dependent
-metabolized by CYP3A isoforms
-Recommended in pregnant women
-Severe rash can occur
-Liver toxicity
-Can induce CYP3A system

27

HIV protease inhibitors

-introduced 1995
-reversible inhibitors of HIV aspartyl protease
-prevents proteolysis of viral polyprotein
-1000 fold higher affinity for HIV protease
-prevents maturation of viral particles
-non-infectious virus produced
-used in HAART

28

Pharmacokinetics of HIV protease inhibitors

-poor oral bioavailability
-substrates for CYP3A4 isozyme of cyt P450
-substrates for P-glycoprotein multi drug efflux pump in endothelial cells of brain - restricts access to CNS
-bind to plasma proteins - alpha 1 acid - glycoprotein

29

Adverse effects of HIV protease inhibitors

-parasthesia, nausea, vomiting, diarrhea
-Diabetes phenotype
-Fat redistribution

30

Resistance of HIV protease inhibitors

Mutations of HIV protease gene

31

Major toxicities and concerns with the HIV protease inhibitor - Lopinavir

GI adverse effects are the most common

32

Major toxicities and concerns with the HIV protease inhibitor
- Ritonavir

Diarrhea, nausea, taste perversion, vomiting, anemia, increased hepatic enzymes, increased triglycerides

Requires refrigeration; take with meals; chocolate milk improves the taste

33

What drug classes should not be administer with any protease inhibitor

Antiarrhythmics, ergot derivatives, antimycobacterial drugs, benzodiazepines, barbiturates, anticoagulants, herbal supplements

**linked to inhibition of CYP isozymes

34

Describe HIV integrase inhibitors - mechanism of action

Integrase binds to viral DNA & catalytically processes 3' ends.

Integrase joins viral and cellular DNA.

Raltegravir blocks strand transfer.

Degradation or recombination and repair.

35

Describe the HIV integrase strand transfer inhibitor - Dolutegravir

-metabolized by UGT1A1 and CYP3A
-inhibits renal transporter OCT2 and so contraindicated with dofetilide and metformin
-rash and hypersensitivity can occur

36

Describe the HIV integrase strand transfer inhibitor - Elvitegravir

-requires boosting
ex. cobicistat (inhibitor of CYP3A4)

37

Describe the HIV integrase strand transfer inhibitor -
Raltegravir

-metabolized by UGT1A1
-Does not interact with Cyt p450 system
-Antacids should be used with caution
-Severe hypersensitivity and rash can occur

38

Describe viral fusion inhibitor

-new class
-Enfuvirtide
-HIV protein gp41 mediates cell fusion
-36 amino acid peptide binds to gp41
-given subcutaneously
-expensive - 25,000 p.a.
-salvage therapy - for multi drug resistant HIV

39

Describe the co-receptor inhibitor: Maraviroc

-specifically binds to host CCR5 (V3 loop) - thus only effective against HIV-1 tropic for CCR5.
-contraindicated in renal impairment
-caution required with hepatic problems
-substrate for CYP3A4
-resistance linked to mutations in gp120 protein

40

Describe the influenza virus

-Flu A and B most common
-Flu A carried in aquatic birds - domestic birds
-Flu A most severe
-No RNA proof-reading - drug resistance
-Spanish flu (type A) pandemic 1918-1919 - 40-100 million died

41

Describe the key proteins of the influenza virus

-(-)ssRNA virus
-aerosol passage
-attack epithelial cells
-Hemagglutinin (Hag) binds to silica acid sugars on cells
-Neuraminidase cleaves sailic residues to release virus
-M2 ion channel - proton channel that modulates pH

42

Influenza virus life cycle

-Hag binds to cell surface
-Mediates endocytosis of particle
-M2 regulates uncoating
-M2 also controls Hag processing
-Release of particles from buds requires neuraminidase

43

Describe neuraminidase inhibitors

-viral neuraminidase - glycoside hydrolase enzyme
-cleave glycosidic linkages on neuraminic (sailic) acid
-permits release of viral particle from host cell
-Zanamivir (inhale); Oseltamivir (oral) - effective prophylaxis and against spread of infection in flu A and B
-Problem - needs to be taken within 6-12 hours**

44

List 2 inhibitors of viral uncoating

Amantadine
Rimantadine

45

Describe Amantadine and Rimantadine (inhibitors of viral uncoating)

-Block M2 channel
-Prevent acidification of viral particle
-Stop release of viral genome and uncoating
-Early therapy effective against influenza A

46

Describe Hepatitis B Virus (HBV)

-most common form (of hepatitis?)
-hepatitis, cirrhosis, carcinoma
-dsDNA virus (but uses reverse transcriptase)
-blood-blood transfer
-2 billion people infected (type B)
-acute liver damage
-vaccination possible
-persistent infection - cccDNA (covalently closed circular)

47

Describe hepatitis C virus

-(-)ssRNA virus
-Difficult to detect symptoms
-blood-blood transmission
-200 million infected
-treatment in patients likely to exhibit cirrhosis

48

Describe interferon treatment

-chronic infection only
-interferon alpha 2a/2b
-raises cell resistance - antiviral state
-innate induction of interferon by high levels of dsRNA or foreign RNA
-elevates MHC1 - presentation to cytotoxic CD8 T cells
-Increases p53 - apoptosis
-Subcutaneous injection: 4-6 months

49

Describe anti-HBV drugs

-use of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
-DNA chain termination
-Lamivudine
-Tenofovir
-Combined with interferon

50

Ribavirin is an anti-HCV drug

-guanosine analogue
-inhibits capping of viral mRNA and viral RNA-dependent RNA polymerase - also inhibits influenza/HIV-1
-hemolytic anemia and range of other side effects
-contraindicated in pregnancy, kidney disease and vascular disease

*Standard therapy now ribavirin plus peg interferon alfa

51

Describe the protease inhibitors that work as anti-HCV drugs

-inhibit NS3/4A protease that cleavers HCV-encoded poly-proteins
-numerous side effects and drug: drug interactions
-CYP3A interactions
-Contraindicated with statins and rifampin

ex. Boceprevir - combined with ribavirin and peginterferon
ex. Telaprevir
ex. Sofosbuvir - inhibits HCV NS5B RNA-dependent RNA polymerase
-combined with ribavirin and peg interferon alfa
-very expensive

52

____ and ____ use reverse transcriptase (RT)

HIV
HBV