Antiviral Agents

Dr. Yunita Sari Pane, MSDr. Yunita Sari Pane, MS

06 August 2009 1

DEPARTEMEN FARMAKOLOGI & TERAPEUTIK

FK USU

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

2

• Steps for Viral Replication

1) adsorption and penetration into cell

2) uncoating of viral nucleic acid

3) synthesis of regulatory proteins

VIRUSES

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

3

ANTIVIRAL AGENTS

• Block viral entry into the cell or must work inside the

cell

• Most agents are pyrimidine or purine nucleoside • Most agents are pyrimidine or purine nucleoside

analogs

4

SITES OF

DRUG

ACTION

5

6

Sites of Drug

Action

7

AntiHerpes Agents

• Acyclovir - prototype

• Valacyclovir

• Famciclovir• Famciclovir

• Penciclovir

• Trifluridine

• Vidarabine

8

9

Mechanism of Action Acyclovir

• An acyclic guanosine derivative

• Phosphorylated by viral thymidine kinase

AntiHerpes Agents

• Di-and tri-phosphorylated by host cellular enzymes

• Inhibits viral DNA synthesis by:

1) competing with dgtp for viral DNA polymerase

2) chain termination

10

11

Mechanism of Resistance

Acyclovir

• Alteration in viral thymidine kinase

• Alteration in viral DNA polymerase

AntiHerpes Agents

• Alteration in viral DNA polymerase

• Cross-resistance with valacyclovir, famciclovir, and

ganciclovir

12

Clinical Uses Acyclovir

• Oral, IV, and Topical formulations

• Cleared by glomerular filtration and tubular secretion

Uses:

AntiHerpes Agents

• Uses:

– Herpes Simplex Virus 1 and 2 (HSV)

– Varicella-zoster virus (VZV)

• Side Effects: nausea, diarrhea, headache, tremors, and

delirium13

Valacyclovir

• L-valyl ester of acyclovir

• Converted to acyclovir when ingested

• M.O.A.: same as acyclovir

AntiHerpes Agents

• M.O.A.: same as acyclovir

• Uses:

– 1) recurrent genital herpes

– 2) herpes zoster infections

• Side Effects: nausea, diarrhea, and headache14

Famciclovir

• Prodrug of Penciclovir (a guanosine analog)

• M.O.A.: same as acyclovir

does not cause chain termination

AntiHerpes Agents

• does not cause chain termination

• Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B

• Side Effects: nausea, diarrhea, and headache

15

Trifluridine

• Trifluridine- fluorinated pyrimidine

– Inhibits viral DNA synthesis same as acyclovir

– Incorporates into viral and cellular DNA

AntiHerpes Agents

– Incorporates into viral and cellular DNA

– Uses: HSV-1 and HSV-2 (topically)

16

Vidarabine

• An adenosine analog

• inhibits viral DNA polymerase

incorporated into viral and cellular DNA

AntiHerpes Agents

• incorporated into viral and cellular DNA

• metabolized to hypoxanthine arabinoside

• Side Effects: GI intolerance and myelosuppression

17

Anti-Cytomegalovirus Agents

• Gancyclovir

• Valgancyclovir

• Cidofovir• Cidofovir

• Foscarnet

• Fomivirsen

18

Ganciclovir

• An acyclic guanosine analog

• requires triphosphorylation for activation

• monophosphorylation is catalyzed by a

Anti-Cytomegalovirus Agents

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 19

• Monovalyl ester prodrug of gancyclovir

• Metabolized by intestinal and hepatic esterases when

administered orally

Valgancyclovir

Anti-Cytomegalovirus Agents

administered orally

• M.O.A.: same as Gancyclovir

• Uses: CMV*

• Side Effect: myelosuppression

20

• A cytosine analog

• phosphorylation not dependent on viral enzymes

• Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6,

Cidofovir

Anti-Cytomegalovirus Agents

• 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 gene21

• An inorganic pyrophosphate

• inhibits viral DNA polymerase, RNA polymerase, and HIV

reverse transcriptase

Foscarnet

Anti-Cytomegalovirus Agents

reverse transcriptase

• does not have to be phosphorylated

• Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV

• Resistance due to mutations in DNA polymerase gene

• Side Effects: hypo- or hypercalcemia and phosphotemia22

• An oligonucleotide

• M.O.A.: binds to mRNA and inhibits protein synthesis

and viral replication

Fomivirsen

Anti-Cytomegalovirus Agents

and viral replication

• Uses: CMV retinitis

• Side effects: iritis and increased intraocular pressure

23

24

25

26

AntiRetroviral Agents

1) Nucleoside Reverse Transcriptase Inhibitors

(NRTIs)

2) Nonnucleoside Reverse Transcriptase 2) Nonnucleoside Reverse Transcriptase

Inhibitors (NNRTIs)

3) Protease inhibitors

27

o Reverse Transcriptase Inhibitors

Zidovudine (AZT)

Didanosine- causes pancreatitis*

Lamivudine- causes pancreatitis

AntiRetroviral Agents

Zalcitabine- causes peripheral neuropathy*

Stavudine- causes peripheral neuropathy*

Abacavir

28

Mechanism of Action Zidovudine (AZT)

• A deoxythymidine analog

• enters the cell via passive diffusion

AntiRetroviral AgentsReverse Transcriptase Inhibitors

• must be converted to the triphosphate form by

mammalian thymidine kinase

• competitively inhibits deoxythymidine triphosphate for

the reverse transcriptase enzyme

• causes chain termination 29

• Due to mutations in the reverse transcriptase gene

• More frequent after prolong therapy and in persons

AntiRetroviral Agents

Mechanism of ResistanceZidovudine (AZT)

Reverse Transcriptase Inhibitors

• More frequent after prolong therapy and in persons

with hiv

30

Clinical Uses Zidovudine

• Available in IV and oral formulations

• activity against HIV-1, HIV-2, and human T cell

AntiRetroviral AgentsReverse Transcriptase Inhibitors

• 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

31

Side Effects Zidovudine

• Myelosuppression, including anemia and

AntiRetroviral Agents

Reverse Transcriptase Inhibitors

neutropenia

• GI intolerance, headaches, and insomnia

32

o Other NRTIs

• Didanosine- synthetic deoxy-adenosine analog; causes

pancreatitis*

• Lamivudine- cytosine analog

AntiRetroviral Agents

• 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

33

o Nucleotide Inhibitors

• Tenofovir

• Adefovir

AntiRetroviral Agents

34

Tenofovir

• An acyclic nucleoside phosphonate analog of

adenosine

• M.O.A.- competively inhibits HIV reverse transcriptase

AntiRetroviral Agents

Nucleotide Inhibitors

• 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 suppression35

Adefovir

• An analog of adenosine monophosphate

• Phosphorylated by cellular kinases

• M.O.A. - Competitively inhibits HBV DNA polymerase

AntiRetroviral Agents

Nucleotide Inhibitors

• M.O.A. - Competitively inhibits HBV DNA polymerase

and results in chain termination after incorporation into

viral DNA

• Uses - Hepatitis B

• Side effects - nephrotoxicity36

o Nonnucleoside Reverse Transcriptase

Inhibitors (NNRTIs)

Nevirapine

Delavirdine

AntiRetroviral Agents

Efavirenz

37

Mechanism of ActionNNRTIs

• Bind to site on viral reverse transcriptase, different from

NRTIs

• results in blockade of RNA and DNA dependent DNA

polymerase activity

AntiRetroviral Agents

polymerase activity

• do not compete with nucleoside triphosphates

• do not require phosphorylation

• these drugs can not be given alone

• substrates and inhibitors of CYP3A4

38

• Nevirapine

prevents transmission of HIV from mother to newborn

when given at onset of labor and to the neonate at

delivery

AntiRetroviral Agents

o NNRTIs

• Delavirdine

teratogenic, therefore can not be given during pregnancy

• Efavirenz

teratogenic, therefore can not be given during pregnancy

39

3. Protease Inhibitors

Indinavir

Ritonavir

Saquinavir

AntiRetroviral Agents

Saquinavir

Nelfinavir

Amprenavir

40

• The protease enzyme cleaves precursor molecules to

produce mature, infectious virions

AntiRetroviral Agents

o Protease Inhibitors

• these agents inhibit protease and prevent the spread

of infection

• These agents cause a syndrome of altered body fat

distribution, insulin resistance, and hyperlipidemia

41

Indinavir and Ritonavir

• M.O.A.: Specific inhibitors of the HIV-1 protease enzyme

• M.O.R.: mediated by expression of multiple and variable

AntiRetroviral AgentsProtease Inhibitors

protease amino acid substitutions

• Side Effects:hyperbilirubinemia

• Contraindications:inhibitor/substrate for CPY3A4, do not

give with antifungal azoles

42

Saquinavir

• A synthetic peptide-like substrate analog

• inhibits HIV-1 protease

AntiRetroviral AgentsProtease Inhibitors

• inhibits HIV-1 protease

• prevents cleavage of viral polyproteins

43

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

AntiRetroviral AgentsProtease Inhibitors

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 44

Fusion Inhibitors

• Enfuvirtide (T-20)- binds to the gp41 subunit of the viral

envelope glycoprotein, preventing the conformational

AntiRetroviral AgentsProtease Inhibitors

changes required for fusion of the viral and cellular

membranes

• By blocking fusion (entry into cell), FUZEON prevents HIV

from infecting CD4 cells

45

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 outside of the cell to prevent HIV from fusing with, and infecting the

CD4 cells in the first place.

from Fuzeon.com

46

Anti-Hepatitis Agents

Lamivudine -Nucleoside Reverse Transcriptase

Inhibitor (NRTI)

Adefovir -Nucleotide Inhibitor

Interferon AlfaInterferon Alfa

Pegylated Interferon Alfa

Ribavirin

47

Interferon Alfa

• Endogenous proteins

• induce host cell enzymes that inhibit viral RNA

translation and cause degradation of viral mRNA and

tRNA

Anti-Hepatitis Agents

Interferons

tRNA

• Bind to membrane receptors on cell surface

• May also inhibit viral penetration, uncoating, mRNA

synthesis, and translation, and virion assembly and

release

48

Interferons

Pegylated Interferon Alfa

• A linear or branced polyethylene gylcol (PEG) moiety is

attached to covalently to interferon

Anti-Hepatitis Agents

attached to covalently to interferon

• Increased half-life and steady drug concentrations

• Less frequent dosing

• Tx chronic hepatitis C in combination with ribavirin

49

Ribavirin

• A guanosine analog

• phosphorylated intracellularly by host enzymes

• inhibits capping of viral messenger RNA

Anti-Hepatitis Agents

• inhibits capping of viral messenger RNA

• inhibits the viral RNA-dependent RNA polymerase

• inhibits replication of DNA and RNA viruses

50

51

Anti-Influenza Agents

Amantadine

Rimantadine

Zanamivir

Oseltamivir

52

Amantadine and Rimantadine

• Cyclic amines

• Inhibit the uncoating of viral RNA therefore inhibiting

replication

Anti-Influenza Agents

replication

• Resistance due to mutations in the RNA sequence coding

for the structural M2 protein

• Used in the prevention and treatment of influenza A

53

Zanamivir and Oseltamivir

• Inhibits the enzyme neuraminidase

• inhibit the replication of influenza A and Influenza B

• treats uncomplicated influenza infections

Anti-Influenza Agents

• treats uncomplicated influenza infections

• administered intranasally

54

55

56

57

58