eli173 slide antiviral

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}

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}

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 cycle targeted by antiviral drugs

1. Fusion inhibitors (enfuvirtide)

2. Inhibit virus uncoating

(ion channel blocker: amantadine, rimantadine)

The stages of the viral life cycle targeted by antiviral drugs

4. Inhibit viral maturation : protease inhibitor (anti HIV drugs : saquinavir & ritonavir)

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}

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,}

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}

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}

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}

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)

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}

Antiretroviral Agents

1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

2) Nonnucleoside Reverse

Transcriptase Inhibitors (NNRTIs)

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

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}

Side Effects

Zidovudine

• _{Myelosuppression, including anemia}

and neutropenia

• _{GI intolerance, headaches, and}

insomnia

Other NRTIs

• _{Didanosine-synthetic deoxy-adenosineanalog; causes}

pancreatitis*

• _{Lamivudine- cytosineanalog}

• _{Zalcitabine-cytosineanalog; causes peripheral}

neuropathy*

• _{Stavudine-thymidineanalog;causes peripheral}

neuropathy*

• _{Abacavir-guanosine analog; more effective than the}

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}

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)

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}

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}

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}

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}

• _{Amprenavircan 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}

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}

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}

Ribavirin

• _{A guanosine analog}

• _{phosphorylated intracellularly by host}

enzymes

• _{inhibits capping of viral messenger RNA}

• _{inhibits the viral RNA-dependent RNA}

polymerase

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}

Zanamivir

and

Oseltamivir

• _{Inhibits the enzyme neuraminidase}

• _{inhibit the replication of influenza A}

and Influenza B

• _{treats uncomplicated influenza}

infections

• _{administered intranasally}