elo173 slide antiviral agents

(1)

Antiviral Agents

! " # !

(2)

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

(3)

•

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

(4)

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

(5)

SITES OF

DRUG

ACTION

(6)

(7)

Sites of Drug

Action

(8)

AntiHerpes Agents

•

Acyclovir -

prototype

•

Valacyclovir

Famciclovir

•

Famciclovir

•

Penciclovir

•

Trifluridine

•

Vidarabine

(9)

(10)

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

(11)

(12)

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

(13)

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

delirium

(14)

Valacyclovir

• L-valyl ester of acyclovir

• Converted to acyclovir when ingested

• M.O.A.: same as acyclovir

AntiHerpes Agents

• Uses:

– 1) recurrent genital herpes

– 2) herpes zoster infections

• Side Effects: nausea, diarrhea, and headache

(15)

Famciclovir

• Prodrug of Penciclovir (a guanosine analog)

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

(16)

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

(17)

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

(18)

Anti-Cytomegalovirus Agents

•

Gancyclovir

•

Valgancyclovir

Cidofovir

•

Cidofovir

•

Foscarnet

•

Fomivirsen

(19)

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

• Uses: CMV*, HSV, VZV,and EBV

(20)

• Monovalyl ester prodrug of gancyclovir

• Metabolized by intestinal and hepatic esterases when

administered orally

Valgancyclovir

administered orally

• M.O.A.: same as Gancyclovir

• Uses: CMV*

(21)

• A cytosine analog

• phosphorylation not dependent on viral enzymes

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

Cidofovir

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

adenovirus, and human papillomavirus

• Side Effects: nephrotoxicity (prevented by admin. of

probenecid)

(22)

• An inorganic pyrophosphate

• inhibits viral DNA polymerase, RNA polymerase, and HIV

reverse transcriptase

Foscarnet

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

(23)

• An oligonucleotide

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

and viral replication

Fomivirsen

and viral replication

• Uses: CMV retinitis

• Side effects: iritis and increased intraocular pressure

(24)

(25)

(26)

(27)

AntiRetroviral Agents

1) Nucleoside Reverse Transcriptase Inhibitors

(NRTIs)

2) Nonnucleoside Reverse Transcriptase

Inhibitors (NNRTIs)

3) Protease inhibitors

(28)

o

Reverse Transcriptase Inhibitors

Zidovudine (AZT)

Didanosine-

causes pancreatitis*

Lamivudine-

causes pancreatitis

Zalcitabine-

causes peripheral neuropathy*

Stavudine-

causes peripheral neuropathy*

Abacavir

(29)

Mechanism of Action

Zidovudine (AZT)

• A deoxythymidine analog

• enters the cell via passive diffusion

Reverse Transcriptase Inhibitors

• must be converted to the triphosphate form by

mammalian thymidine kinase

• competitively inhibits deoxythymidine triphosphate for

the reverse transcriptase enzyme

(30)

• Due to mutations in the reverse transcriptase gene

More frequent after prolong therapy and in persons

Mechanism of Resistance

Zidovudine (AZT)

• More frequent after prolong therapy and in persons

with hiv

(31)

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

(32)

Side Effects

Zidovudine

• Myelosuppression, including anemia and

neutropenia

• GI intolerance, headaches, and insomnia

(33)

o

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

(34)

o

Nucleotide Inhibitors

•

Tenofovir

•

Adefovir

(35)

Tenofovir

• An acyclic nucleoside phosphonate analog of

adenosine

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

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 suppression

(36)

Adefovir

• An analog of adenosine monophosphate

• Phosphorylated by cellular kinases

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

Nucleotide Inhibitors

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

and results in chain termination after incorporation into

viral DNA

• Uses - Hepatitis B

(37)

o

Nonnucleoside Reverse Transcriptase

Inhibitors (NNRTIs)

Nevirapine

Delavirdine

Efavirenz

(38)

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

(39)

•

Nevirapine

prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at

delivery

o

NNRTIs

•

Delavirdine

teratogenic, therefore can not be given during pregnancy

•

Efavirenz

teratogenic, therefore can not be given during pregnancy

(40)

3. Protease Inhibitors

Indinavir

Ritonavir

Saquinavir

Nelfinavir

Amprenavir

(41)

• The protease enzyme cleaves precursor molecules to

produce mature, infectious virions

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

(42)

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 Agents

Protease Inhibitors

protease amino acid substitutions

• Side Effects:hyperbilirubinemia

• Contraindications:inhibitor/substrate for CPY3A4, do not

give with antifungal azoles

(43)

Saquinavir

• A synthetic peptide-like substrate analog

inhibits HIV-1 protease

Protease Inhibitors

• inhibits HIV-1 protease

• prevents cleavage of viral polyproteins

(44)

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 Inhibitors

• Less cross-resistance with Amprenavir

• Side Effects: diarrhea and flatulence

• Amprenavir can cause Stevens-Johnson syndrome

(45)

Fusion Inhibitors

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

envelope glycoprotein, preventing the conformational

Protease Inhibitors

changes required for fusion of the viral and cellular

membranes

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

from infecting CD4 cells

(46)

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.

) *+

, * -*+

(47)

Anti-Hepatitis Agents

Lamivudine

-Nucleoside Reverse Transcriptase

Inhibitor (NRTI)

Adefovir

-Nucleotide Inhibitor

Interferon Alfa

Pegylated Interferon Alfa

Ribavirin

(48)

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

(49)

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

(50)

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

(51)

(52)

Anti-Influenza Agents

Amantadine

Rimantadine

Zanamivir

Oseltamivir

(53)

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

(54)

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

(55)

(56)

(57)

(58)