Lecture 14 - Antivirals Flashcards
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
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
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)
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
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)
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
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
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.
Describe CMV
- CMV a major problem in immune-compromised patients (organ transplantation)
- Can lead to liver failure, colitis and retinitis (inflammation of retina)
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)
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
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
Origin of HIV:
“USA first” model
Probability = ?
0.01%
Origin of HIV:
“Haiti first” model
Probability = ?
99.8%
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
NRTI
Nucleoside/nucleotide reverse transcriptase inhibitors
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
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
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
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
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
Describe the NRTI - Tenofovir
- acyclic analogue of adenosine
- long half-life allows once a day dosing
- GI complaints and renal dysfunction contraindicated
NNRTI
Non-Nucleoside/nucleotide reverse transcriptase inhibitors
Describe NNRTIs
- non-competitive inhibitors of HIV-1 reverse transcriptase
- no activation required
- no effect on bone marrow or mitochondrial DNA polymerase
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)
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
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
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
Adverse effects of HIV protease inhibitors
- parasthesia, nausea, vomiting, diarrhea
- Diabetes phenotype
- Fat redistribution
Resistance of HIV protease inhibitors
Mutations of HIV protease gene
Major toxicities and concerns with the HIV protease inhibitor - Lopinavir
GI adverse effects are the most common
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
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
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.
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
Describe the HIV integrase strand transfer inhibitor - Elvitegravir
- requires boosting
ex. cobicistat (inhibitor of CYP3A4)
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
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
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
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
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
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
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**
List 2 inhibitors of viral uncoating
Amantadine
Rimantadine
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
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)
Describe hepatitis C virus
- (-)ssRNA virus
- Difficult to detect symptoms
- blood-blood transmission
- 200 million infected
- treatment in patients likely to exhibit cirrhosis
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
Describe anti-HBV drugs
- use of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
- DNA chain termination
- Lamivudine
- Tenofovir
- Combined with interferon
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
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
____ and ____ use reverse transcriptase (RT)
HIV
HBV
