Lecture 14 - Antivirals Flashcards Preview

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Flashcards in Lecture 14 - Antivirals Deck (52)
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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