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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

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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Antiretroviral Agents

1) Nucleoside Reverse Transcriptase

Inhibitors (NRTIs)

2) Nonnucleoside Reverse

Transcriptase Inhibitors (NNRTIs)

3)Protease inhibitors

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Zanamivir and Oseltamivir

• Inhibits the enzyme neuraminidase

• inhibit the replication of influenza A

and Influenza B

• treats uncomplicated influenza

infections

• administered intranasally

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