ANTI-VIRAL DRUGS

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ANTI-VIRAL DRUGS
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Objectives

• The major mechanisms of antiviral action
• Classes of drugs used for treatment of
• Herpes, varicella, cytomegalovirus
• HIV
• Viral hepatitis
• Influenza
• Important representative drugs

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Characteristics of Viruses

• Obligate intracellular parasites
• Single- or double-stranded DNA or RNA viruses,
  surrounded by a protein coat
• DNA viruses pox, herpes, adeno, hepadno
• RNA viruses rubella, rabies, polio, influenza
• Retroviruses HIV, hepatitis B
• Host enzymes and intermediary metabolites are
  required for viral replication
• Vaccination is the most effective preventive
  therapy

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Viral Replication
DNA, RNA Viruses
Nucleotides
Amino acids
vProteins
vDNA
vmRNA
hPolymerase
hRibosomes
Other
vCapsid
vKinases vPolymerases
Retroviruses
vRNA
Host Genome
vDNA
vReverse Transcriptase
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Nucleosides

• Nitrogen-containing ring structure
• Purines
• Adenosine, Guanosine
• Pyridimidines
• Cytosine, Thymidine
• Uracil (RNA)
• Sugar
• Ribose (RNA)
• 2-Deoxyribose (DNA)

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• Kinases
• Phosphorylate the sugar
• at the 5 position
• Different enzymes may
• catalyze the first, second, or
• third phosphorylation
• The phosphorylated product
• is called a nucleotide
• Mononucleotides
• Dinucleotides
• Trinucleotides

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Why Not Use Nucleotides Instead of Nucleosides?

• The phosphate groups on nucleotides are ionized
  at body pH, and ionized compounds do not cross
  membranes readily.
• Nucleosides can enter cells via nucleoside
  transporters and/or passive diffusion.
• A few mononucleotides do penetrate cells
  sufficiently to have antiviral action.

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• Polymerases
• Catalyze the addition of a
• nucleotide to a chain
• 5 to 3 addition
• Liberate inorganic
• pyrophosphate (PPi)

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Antiviral Nucleoside Analogs

• Phosphorylated within cells.
• Viral kinases may preferentially phosphorylate
  the analogs explains selective toxicity.
• The nucleoside analogs may have modifications of
  the base or the sugar.
• Sugar modifications are more common
• Base modifications associated with toxicity
• The phosphorylated nucleotide analogs accumulate
  within cells.
• Compete with natural nucleotides for polymerases
  and incorporation into viral DNA or RNA

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A Quick Think

• Nucleic acid polymers are built by adding
  nucleotide triphosphates to the 3 hydroxyl group
  of a growing polymer.
• What will happen if the last nucleotide added has
  no 3 hydroxyl group?

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Acyclic Nucleosides(Many of the anti-herpes
agents)
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Dideoxy Nucleosides(Many of the anti-HIV
agents)
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Viral Enzymes Targeted by Nucleoside Analogs

• Kinases that catalyze 5-phosphorylation
• Herpes
• Varicella
• Cytomegalovirus

• Polymerases that form nucleic acid chains
• 5 to 3 linkage of nucleotide analogs
• Reverse transcriptase (HIV or HBV)

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General Pharmacology of Antiviral Nucleoside Drugs

• Most are orally effective
• Prodrugs may increase blood levels
• Valacyclovir, valgancyclovir, adefovir divipoxil
• Half-life of 2-3 hours for non-phosphorylated
  drug
• Enter cells by passive diffusion or facilitated
  transport
• Generally not metabolized excreted in urine

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Adverse Effects of Antiviral Nucleosides

• Acyclic nucleosides have a low incidence of
  adverse effects (nausea, drowsiness)
• Unique to dideoxy drugs (anti-retroviral
  drugs)
• Myopathies, neuropathies, myelosuppression
• Lactic acidosis, steatosis, pancreatitis
• Explained by inhibition of a mitochondrial DNA
  polymerase?
• Concern regarding teratogenicity, carcinogenity
• Especially those with modified bases or arabinose
  as a sugar
• Idoxuridine, vidarabine

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Properties of Protease Inhibitors

• Prevent proteolytic cleavage of essential viral
  proteins into mature, active forms.
• Specific for HIV proteases or HCV aspartyl
  proteases
• Unreliable as sole therapy use in combination
  chemotherapy
• Resistance to one PI may be overcome with another
  PI

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General Pharmacology of Protease Inhibitors

• High molecular weight drugs, but orally effective
• Availability of most dependent on dosing with or
  without food fatty meals
• Movement across membranes partially dependent on
  transporters
• MDR1 (p-glycoprotein) keeps CNS concentrations
  low

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PI Metabolism and Boosted Therapy

• Metabolized by cytochrome P-450 enzymes drug
  interactions possible
• Duration of action is highly variable
• Depends on CYP expression the individual PI
• Boosted therapy uses a drug that is inhibitory
  to CYP enzymes to prolong the t1/2 of another PI
• Example Ritonavir lopinavir

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Class-Related Toxicities of PIs

• GI symptoms
• Metabolic complications
• Fat redistribution (buffalo hump)
• Dyslipidemias
• Insulin resistance

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Antiviral Drugs Indicated for Herpes and Related
Viruses

• Herpes, Varicella, Cytomegalovirus

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Anti-Herpes Drugs

• Acyclovir
• Targets Herpes thymidine kinase
• Acyclovir triphosphate competes with GTP for
  polymerase
• Terminates chain elongation if added to DNA

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Other Drugs Used for Herpes and Varicella

• Valacyclovir
• Pro-drug of acyclovir (valine ester)
• Rapidly hydrolyzed in bloodstream to release
  acyclovir
• More than doubles the bioavailability of
  acyclovir

• Penciclovir (topical)
• Used topically for cold sores (Herpes labilis)
• Famciclovir a pro-drug of penciclovir

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Anti-Cytomegalovirus (CMV) Nucleoside Drugs

• Ganciclovir is prototype
• Initial 5- phosphorylation also by a kinases
  from Herpes and CMV
• Valganciclovir
• Pro-drug formulation of ganciclovir

• Cidofovir
• A mononucleotide
• Bypasses initial 5 phosphorylation step
• May be active against ganciclovir-resistant
  strains
• Nephrotoxic give IV with probenecid hydration

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• Polymerases
• Catalyze the addition of a
• nucleotide to a chain
• 5 to 3 addition
• Liberate inorganic
• pyrophosphate

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Foscarnet

• Pyrophosphate analog (polymerase inibitor)
• Relatively broad antiviral spectrum
• Major adverse effects
• Nephrotoxicity
• Hypocalcemia
• Headaches

• Toxicity limits major indication to
  ganciclovir-resistant CMV infection

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Human Immunodeficiency Virus

• HIV

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General Principles of HIV Therapy

• Chronic infection
• Addressed with combination chemotherapy of 3 or
  more drugs with different mechanisms of action
• Agents selected by viral sensitivity and patient
  factors
• Monitor for resistance and modify agents used as
  needed

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Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)

• Zidovudine
• Azidothymidine (AZT, ZDV)
• Prototype
• Phosphorylated intracellularly
• AZT triphosphate competes with thymidine
  triphosphate for reverse transcriptase binding
  sites

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Other Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)

• Didanosine (ddI)
• Stavudine (d4T ddT)
• Lamivudine (3TC)
• Also indicated for hepatitis B
• Zalcitabine (ddC)
• Telbivudine
• Thymidine analog

• Abacavir
• ddG prodrug
• Hypersensitivity reactions
• Tenofovir
• Acyclic AMP analog
• A mononucleotide
• Emtricitabine
• Cytosine analog

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Quick Think

• NRTIs are used in combination for HIV therapy.
• Which one of the two combinations shown below is
  most likely to be effective in HIV treatment?
• Lamivudine (3TC) plus zalcitabine (ddC)
• Lamivudine (3TC) plus stavudine (d4T)

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Commercial NRTI Combinations

• Lamivudine (3TC) Zidovudine (AZT)
• Emtricitabine (Cytosine) Tenofovir (AMP)
• Abacavir (Guanosine) Lamivudine (3TC)
• Abacavir (G) Lamivudine (3TC) Zidovudine (AZT)

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Class-Related Toxicities of NRTIs

• GI intolerance
• Peripheral neuropathy
• Lactic acidosis, pancreatitis
• Bone marrow suppression
• Lipotrophy (stavudine, zidovudine)
• Renal toxicity (tenofovir)

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Protease Inhibitors (PIs) Indicated for HIV
Infection

• For HIV
• Indinavir Saquinavir
• Ritonavir Nelfinavir
• Amprenavir Lopinavir
• Atazanavir Fosamprenavir
• Darunavir Tipranavir

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• Saquinavir was the first protease inhibitor
  developed
• Complex chemical structures based on structure
  of protein hydrolyzed

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Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• Nevirapine
• (structure shown)
• Delavirdine
• Efavirenz
• Etravirine
• Rilpirivine

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Properties of NNRTIs

• Unreliable as sole therapy
• Used in combination with NRTIs, PIs, other drugs
• Metabolized by cytochrome P-450 enzymes drug
  interactions are possible

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Class-Related Toxicities of NNRTIs

• Serious skin rashes
• Liver toxicity
• Dyslipidemias

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Fusion Inhibitors

• Enfuvirtide
• Binds HIV gp41 (has affinity for CD4 on cell
  surfaces)
• Prevents entry of the virus into CD4 cells
• Peptide drug must be given by subcutaneous
  injection
• Adverse effects
• Injection site reactions, GI symptoms, myalgias

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Maraviroc

• CCR5 chemokine co-receptor antagonist
• Prevents viral entry into cells
• Only effective for HIV strains that have an
  affinity for CCR5
• CCR5-tropic viruses
• Orally effective
• CYP 3A substrate drug interactions
• GI intolerance and hepatotoxicity
• Potential for cardiovascular effects

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Raltegravir

• An HIV integrase inhibitor blocks insertion of
  viral DNA into host genome
• Orally effective
• Metabolized by glucuronidation (not cytochromes
  P-450)
• Adverse effects include GI symptoms, headache,
  fever

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Elvitegravir

• Recently developed integrase inhibitor
• A CYP3A4 substrate
• Commercial product (Stribild) includes
  cobicistat to inhibit CYP3A4
• An example of boosted integrase inhibitor
  activity

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Complications of HIV Therapy

• Patient adherence is vital for long-term
  suppression
• Huge pill burden because of multiple drugs used
  in combination
• Many are CYP substrates/inducers
• May interfere with other drug therapy
• Example tuberculosis therapy

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Overview of Anti-HIV Therapy
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Viral Hepatitis
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Nucleoside Analogs for Viral Hepatitis

• Hepatitis C
• Ribavirin
• Hepatitis B (a retrovirus)
• Adofovir
• Lamivudine
• Entacavir
• Telbivudine

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Viral Hepatitis C

• Ribavirin (modified guanosine base)
• Drug of choice for hepatitis C
• Used in combination with interferons
• PIs recently developed bocepravir, telapravir
• Aerosol for Respiratory Syncytial Virus (RSV)
  infections
• Only indicated for children
• Deterioration of respiratory function is possible
• Prophylaxis with palivizumab (Synagis)
• Hemolytic anemia most serious toxicity
• FDA pregnancy class X

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Nucleosides for Viral Hepatitis B

• Adefovir
• Dipivoxil prodrug formulation
• Acyclic adenosine mononucleotide
• Half-life 7.5 hr
• Can cause lactic acidosis, enlarged liver
• Also effective for HIV

• Entacavir
• A guanosine nucleotide analog
• Some HIV drugs have FDA approval for HBV
• Lamivudine
• Tenofovir

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Interferons

• a, ß, ? classes
• Indicated primarily for hepatitis B, C
• Some cancers may respond
• Pegylation (conjugation with polyethylene glycol)
  extends half-life of the peptides
• Flu-like symptoms major adverse effect
  myelosuppression is possible at high dose

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Agents for Viral Influenza
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Neuraminidase Inhibitors

• Oseltamivir

• Zanamivir
• Relenza
• Given by inhalation
• Not recommended for patients with asthma or COPD

• Tamiflu
• Oral pro-drug

• Indicated for early symptoms of influenza
• Oseltamivir has been approved for prophylaxis
• Not to replace immunization
• Potential value in avian/swine flu epidemics

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Viral Uncoating Inhibitors

• Amantadine
• Renal elimination
• Anti-Parkinson activity
• Insomnia, dizziness, depression are major adverse
  effects

• Rimantadine
• Hepatic metabolism is major means of elimination
• Better tolerated than amantadine

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Properties of Uncoating Inhibitors

• Initially approved for prophylaxis
• Later recognized to provide some symptomatic
  relief
• 2006-07 Influenza Season
• Testing by the CDC and in Canada indicates high
  levels of resistance to amantadine and
  rimantidine

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Review of Antiviral Drug Mechanisms of Action
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Review of Antivirals by Indication

• Herpes, Varicella
• Acyclovir
• Valacyclovir
• Penciclovir
• Famciclovir
• Ganciclovir
• Valganciclovir

• Cytomegalovirus
• Ganciclovir
• Valgancyclovir
• Cidofovir
• Foscarnet

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Overview of Anti-HIV Drugs

• Zidovudine and other NRTIs (9, and combination
  products)
• Protease inhibitors
• PIs (10, and combo products)
• Non-nucleoside reverse transcriptase inhibitors,
  NNRTIs (5)

• Raltegravir (integrase inhibitor)
• Entry inhibitors
• Enfuvirtide (fusion inhibitor) Maraviroc (CCR5
  receptor antagonist)

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Drugs for Viral Hepatitis

• Interferons
• a, ß, ? types
• Pegylation increases duration of action
• Nucleoside Analogs
• Ribavirin (Hepatitis C)
• Adofovir, etc. (Hepatitis B)
• Protease Inhibitors (Hepatitis C)
• Bocepravir, teleprevir

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Drugs for Influenza

• Neuraminidase inhibitors
• Primarily to relieve symptoms
• Oseltamivir
• Zanamivir

• Uncoating inhibitors
• Primarily for prophylaxis
• Amantadine
• Rimantadine

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Topical Antiviral Drugs

• Skin infections
• Acyclovir
• Penciclovir
• Docosanol

• Ophthalmic infections
• Ganciclovir
• Trifluridine

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Recommend Vaccination

• Influenza - especially for children and elderly
• Varicella zoster (shingles) for old codgers

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Questions?