12/4/2010
1
ANTIVIRAL
Viruses
• Obligate intracellular parasites
• Consist of a core genome in a protein shell and some are surrounded by a lipoprotein
• lack a cell wall and cell membrane
• do not carry out metabolic processes
• Replication depends on the host cell machinery
12/4/2010
2
Viruses• Steps for Viral Replication
1) adsorption and penetration into cell
2) uncoating of viral nucleic acid
3) synthesis of regulatory proteins
4) synthesis of RNA or DNA
5) synthesis of structural proteins
6) assembly of viral particles
7) release from host cell
Antiviral Agents
• Block viral entry into the cell or must
work inside the cell
• Most agents are pyrimidine or purine
nucleoside analogs
12/4/2010
3
The stages of the viral life cycle
targeted by antiviral drugs
1. Attachment and entry
2. Virus become uncoated
3. Genome replication
4. Viral genes are transcribed (RNA synthesis)
5. Virally coded RNA is translated into protein on host
cell ribosomes
6. Virion form (viral particle), which release from the
host cell
The stages of the viral life cycletargeted by antiviral drugs
1. Fusion inhibitors (enfuvirtide)
2. Inhibit virus uncoating (ion channel blocker: amantadine, rimantadine)
3. Inhibit viral genome replication(polymerase inhibitor: acyclovir;reverse transcriptase: zidovudine &efavirenz)
12/4/2010
4
The stages of the viral life cycletargeted by antiviral drugs
4. Inhibit viral maturation : protease
inhibitor (anti HIV drugs : saquinavir &
ritonavir)
5. Block the relase of virus particles from
the host cell: neuramidase inhibitors
12/4/2010
5
12/4/2010
6
Antiherpes Agents
• Acyclovir- prototype
• Valacyclovir
• Famciclovir
• Penciclovir
• Trifluridine
• Vidarabine
Mechanism of Action
Acyclovir
• an acyclic guanosine derivative
• Phosphorylated by viral thymidine kinase
• Di-and tri-phosphorylated by host cellular
enzymes
• Inhibits viral DNA synthesis by:
– 1) competing with dGTP for viral DNA polymerase
– 2) chain termination
12/4/2010
7
12/4/2010
8
Mechanism of Resistance
Acyclovir
• Alteration in viral thymidine kinase
• Alteration in viral DNA polymerase
• Cross-resistance with valacyclovir,
famciclovir, and ganciclovir
Clinical Uses
Acyclovir
• Oral, IV, and Topical formulations
• Cleared by glomerular filtration and tubular secretion
• Uses:
–Herpes Simplex Virus 1 and 2 (HSV)
–Varicella-zoster virus (VZV)
• Side Effects: nausea, diarrhea, headache, tremors, and delirium
12/4/2010
9
Valacyclovir
• L-valyl ester of acyclovir
• Converted to acyclovir when ingested
• M.O.A.: same as acyclovir
• Uses:
–1) recurrent genital herpes
–2) herpes zoster infections
• Side Effects: nausea, diarrhea, and headache
Famciclovir
• Prodrug of penciclovir (a guanosine
analog)
• M.O.A.: same as acyclovir
• does not cause chain termination
• Uses: HSV-1, HSV-2, VZV, EBV, and
hepatitis B
• Side Effects: nausea, diarrhea, and headache
12/4/2010
10
Trifluridine
• Trifluridine- fluorinated pyrimidine
–inhibits viral DNA synthesis same as
acyclovir
–incorporates into viral and cellular DNA
–Uses: HSV-1 and HSV-2 (topically)
Vidarabine
• An adenosine analog
• inhibits viral DNA polymerase
• incorporated into viral and cellular DNA
• metabolized to hypoxanthine arabinoside
• Side Effects: GI intolerance and
myelosuppression
12/4/2010
11
Anti-Cytomegalovirus Agents
• Gancyclovir
• Valgancyclovir
• Cidofovir
• Foscarnet
• Fomivirsen
Ganciclovir
• An acyclic guanosine analog
• requires triphosphorylation for activation
• monophosphorylation is catalyzed by a
phosphotransferase in CMV and by
thymidine kinase in HSV cells
• M.O.A.: same as acyclovir
• Uses: CMV*, HSV, VZV,and EBV
• Side Effect: myelosuppression
12/4/2010
12
Valgancyclovir
• Monovalyl ester prodrug of gancyclovir
• Metabolized by intestinal and hepatic
esterases when administered orally
• M.O.A.: same as gancyclovir
• Uses: CMV*
• Side Effect: myelosuppression
Cidofovir
• A cytosine analog
• phosphorylation not dependent on viral
enzymes
• Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6,
adenovirus, and human papillomavirus
• Side Effects: nephrotoxicity (prevented by
admin. of probenecid)
• Resistance: mutation in DNA polymerase gene
12/4/2010
13
Foscarnet• An inorganic pyrophosphate
• inhibits viral DNA polymerase, RNA polymerase,
and HIV reverse transcriptase
• does not have to be phosphorylated
• IV only
• Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV
• Resistance due to mutations in DNA polymerase
gene
• Side Effects: hypo- or hypercalcemia and
phosphotemia
Fomivirsen
• An oligonucleotide
• M.O.A.: binds to mRNA and inhibits
protein synthesis and viral replication
• Uses: CMV retinitis
• Side effects: iritis and increased
intraocular pressure
12/4/2010
14
12/4/2010
15
Antiretroviral Agents
1) Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
2) Nonnucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
3)Protease inhibitors
12/4/2010
16
Reverse Transcriptase Inhibitors
• Zidovudine (AZT)
• Didanosine- causes pancreatitis*
• Lamivudine- causes pancreatitis
• Zalcitabine- causes peripheral neuropathy*
• Stavudine- causes peripheral neuropathy*
• Abacavir
Mechanism of Action
Zidovudine (AZT)
• A deoxythymidine analog
• enters the cell via passive diffusion
• must be converted to the triphosphate form
by mammalian thymidine kinase
• competitively inhibits deoxythymidine
triphosphate for the reverse transcriptase
enzyme
• causes chain termination
12/4/2010
17
Mechanism of Resistance
Zidovudine
• Due to mutations in the reverse
transcriptase gene
• more frequent after prolong therapy
and in persons with HIV
Clinical Uses
Zidovudine
• Available in IV and oral formulations
• activity against HIV-1, HIV-2, and human
T cell lymphotropic viruses
• mainly used for treatment of HIV,
decreases rate of progression and
prolongs survival
• prevents mother to newborn
transmission of HIV
12/4/2010
18
Side Effects
Zidovudine
• Myelosuppression, including anemia
and neutropenia
• GI intolerance, headaches, and
insomnia
Other NRTIs
• Didanosine- synthetic deoxy-adenosine analog; causes
pancreatitis*
• Lamivudine- cytosine analog
• Zalcitabine- cytosine analog; causes peripheral
neuropathy*
• Stavudine- thymidine analog;causes peripheral
neuropathy*
• Abacavir- guanosine analog; more effective than the
other agents; fatal hypersensitivity reactions can occur
12/4/2010
19
Nucleotide Inhibitors
• Tenofovir
• Adefovir
Tenofovir
• An acyclic nucleoside phosphonate
analog of adenosine
• M.O.A.- competively inhibits HIV reverse
transcriptase and causes chain
termination after incorporation into DNA
• Uses – in combination with other
antiretrovirals for HIV-1 suppression
12/4/2010
20
Adefovir
• An analog of adenosine monophosphate
• Phosphorylated by cellular kinases
• M.O.A. - Competitively inhibits HBV DNA
polymerase and results in chain
termination after incorporation into viral
DNA
• Uses - Hepatitis B
• Side effects - nephrotoxicity
Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• Nevirapine
• Delavirdine
• Efavirenz
12/4/2010
21
Mechanism of Action
NNRTIs• Bind to site on viral reverse transcriptase, different
from NRTIs
• results in blockade of RNA and DNA dependent DNA
polymerase activity
• do not compete with nucleoside triphosphates
• do not require phosphorylation
• these drugs can not be given alone
• substrates and inhibitors of CYP3A4
Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• Nevirapine- prevents transmission of HIV
from mother to newborn when given at
onset of labor and to the neonate at
delivery
• Delavirdine- teratogenic, therefore can
not be given during pregnancy
• Efavirenz- teratogenic, therefore can not
be given during pregnancy
12/4/2010
22
Protease Inhibitors
• Indinavir
• Ritonavir
• Saquinavir
• Nelfinavir
• Amprenavir
Protease Inhibitors
• The protease enzyme cleaves precursor
molecules to produce mature, infectious
virions
• Inhibit protease and prevent the spread
of infection
• These agents cause a syndrome of
altered body fat distribution, insulin
resistance, and hyperlipidemia
12/4/2010
23
Indinavir and Ritonavir
• M.O.A.: Specific inhibitors of the HIV-1
protease enzyme
• M.O.R.: mediated by expression of multiple
and variable protease amino acid
substitutions
• Side Effects:hyperbilirubinemia
• Contraindications:inhibitor/substrate for
CPY3A4, do not give with antifungal azoles
Saquinavir
• A synthetic peptide-like substrate analog
• inhibits HIV-1 protease
• prevents cleavage of viral polyproteins
12/4/2010
24
Nelfinavir and Amprenavir
• M.O.A.: Specific inhibitors of the HIV-1 protease enzyme
• M.O.R.: mediated by expression of multiple and variable protease amino acid substitutions
• Less cross-resistance with Amprenavir
• Side Effects: diarrhea and flatulence
• Amprenavir can cause Stevens-Johnson syndrome
• Contraindications:inhibitor/substrate for CPY3A4
Fusion Inhibitors
• Enfuvirtide (T-20)- binds to the gp41 subunit
of the viral envelope glycoprotein, preventing
the conformational changes required for
fusion of the viral and cellular membranes
• By blocking fusion (entry into cell), FUZEON
prevents HIV from infecting CD4 cells
12/4/2010
25
Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)
classes prevent the replication of HIV by working inside CD4 cells after they have been infected with HIV. The drugs in these three
classes then target specific steps in the replication process to prevent the creation of new HIV particles.
Fusion inhibitors differ from these drugs because they work on the outside of the cell to prevent HIV from fusing with, and infecting
the CD4 cells in the first place.
from Fuzeon.com
Anti-Hepatitis Agents
• Lamivudine -Nucleoside Reverse
Transcriptase Inhibitor (NRTI)
• Adefovir -Nucleotide Inhibitor
• Interferon Alfa
• Pegylated Interferon Alfa
• Ribavirin
12/4/2010
26
Interferons
• Interferon Alfa
• Endogenous proteins
• induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA
• Bind to membrane receptors on cell surface
• May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release
Interferons
• Pegylated interferon Alfa
• A linear or branced polyethylene gylcol (PEG) moiety is attached to covalently to interferon
• Increased half-life and steady drug concentrations
• Less frequent dosing
• Tx chronic hepatitis C in combination with ribavirin
12/4/2010
27
Ribavirin
• A guanosine analog
• phosphorylated intracellularly by host
enzymes
• inhibits capping of viral messenger RNA
• inhibits the viral RNA-dependent RNA
polymerase
• inhibits replication of DNA and RNA viruses
12/4/2010
28
Anti-Influenza Agents
• Amantadine
• Rimantadine
• Zanamivir
Amantadine and Rimantadine
–cyclic amines
– inhibit the uncoating of viral RNA therefore
inhibiting replication
–resistance due to mutations in the RNA
sequence coding for the structural M2
protein
–used in the prevention and treatment of
Influenza A
12/4/2010
29
Zanamivir and Oseltamivir
• Inhibits the enzyme neuraminidase
• inhibit the replication of influenza A
and Influenza B
• treats uncomplicated influenza
infections
• administered intranasally
Thank you