AntiviralsLect 7,8 Sadia Anjum

Targets for Anti-viral therapy

1. viral attachment to cell and fusion (fusion inhibitors)

2. protein translation in infected cells (interferon)

3. protein processing (specific protease inhibitors)

4. DNA synthetic enzymes (reverse transcriptase inhibitors, DNA polymerase inhibitors)

5. DNA integrase

6. Immune system (effective vaccines, restore immune surveillance)

Targets for Anti-viral therapy

Interferons

Interferons are glycoproteins that come in 3 varieties:

ά (made in leukocytes) β (made in fibroblasts)γ (made in T cells) activated T cells produce g interferon

to modulate the immune response

induced by viral infection, IL1, IL2, TNF

Cytokine signaling pathway

Multiple Pathways of Interferon Action

Clinical use of Interferonalpha interferon FDA approved:

◦ genital warts (papillomavirus) note: resiquimod has also been shown to be effective

◦ hepatitis B and C◦ Kaposi’s sarcoma (HSV VIII)

Toxicity◦ fever, fatigue, marrow suppression, depression,

acute influenza like symptoms◦ about 10-20% discontinue therapy due to

toxicity

Hepatitis C Chronic hepatitis C virus (HCV) infection affects 2.7 million

people in the United States.

Cirrhosis of the liver resulting from chronic HCV infection is the leading reason for liver transplantation in the U.S.

Drug treatments such as interferon and ribavirin are not very effective

HCV protease inhibitors are a promising new class of antivirals for this disease

BILN 2061 (Boehringer) looked good but appears to have cardiovascular toxicity and is on hold

VX-950 (Vertex Pharmaceuticals) is now in phase II trials and looks promising

RibavirinA guanosine analogphosphorylated intracellularly by host enzymes inhibits capping of viral messenger RNA inhibits the viral RNA-dependent RNA polymerase inhibits replication of DNA and RNA viruses

Ribavirin antiviral HCV/Dengue

Telaprevir (VX-950) with peg-IFN looks promising in clinical trials

Anti-influenza virus drugs Amantadine, Rimantadine

◦ cyclic amines◦ inhibit the uncoating of viral RNA therefore inhibiting replication◦ only active against influenza A

◦ blocks the influenza M2 ion channel on endosomes and prevents passage of H+ ions required for acidification and viral uncoating

◦ mild CNS effects

Zanamivir, Oseltamivir◦ active against both influenza A and B◦ inhibits influenza viral neuraminidase.◦ Neuraminidase must cleave terminal sialic acid residues on receptors recognized by viral

hemagglutinin. ◦ Without this cleavage, virus remains trapped on infected cells --no release of infectious particles◦ treats uncomplicated influenza infections◦ administered intranasally

Anti-influenza

Targets for treatment of HIV (anti-retroviral drugs

Antiretroviral Agents1) Nucleoside Reverse Transcriptase

Inhibitors (NRTIs)

2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

3)Protease inhibitors

Antivirals: Purine NucleosidesAgent Antiviral Activityguanines

acyclovir HSV 1 & 2, VZVganciclovir (DHPG) CMV retinitis and systemic

CMV infectionribavirin (RTCD) Influenza types A and B,

RSV, LV, HVadenosines

didanosine (ddl) HIVvidarabine (Ara-A) HSV, herpes zoster

Antivirals: Pyrimidine Nucleosides

Agent Antiviral Activitycytosines

lamivudine (3TC) HIVzalcitabine (ddC) HIV

thymineidoxuridine (IDU) HSVstavudine (d4T) HIVtrifluridine HSVzidovudine (AZT) HIV

Zidovudine (AZT) RTase inhibitor

A deoxythymidine analogenters the cell via passive diffusionmust be converted to the

triphosphate form by mammalian thymidine kinase

competitively inhibits deoxythymidine triphosphate for the reverse transcriptase enzyme

causes chain termination

mechanism◦selective reverse transcriptase inhibitor

Zidovudine (AZT) RTase inhibitor

Mechanism of selective toxicity of AZT

AZT concentration (uM)

DNAsynthesis

Zidovudinemechanism

◦ selective reverse transcriptase inhibitorpharmacokinetics:

◦ orally active, penetrates CSF toxicity:

◦ bone marrow depression (anemia, leukopenia)◦ headache, nausea, myopathy, anorexia, fatigue

therapeutic effects:◦ increase CD4+ T cells partially restoring immune system◦ reverses AIDS dementia

resistance: major problem◦ RTase mutations

Lamivudine (3TC)similar to zidovudineresistance develops quickly: selects

for met184val mutation in RTaselamivudine + zidovudine combination

dramatically slows resistance development

NNRTIs(non-nucleosidereverse transcriptaseinhibitors)

NevirapineDelavirdineEfavirenz

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 triphosphatesdo not require phosphorylation these drugs can not be given aloneNevirapine- prevents transmission of HIV from

mother to newborn when given at onset of labor and to the neonate at delivery

Protease InhibitorsThe protease enzyme cleaves

precursor molecules to produce mature, infectious virions

these agents inhibit protease and prevent the spread of infection

These agents cause a syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia

Indinavir and Ritonavir Specific inhibitors of the HIV-1 protease enzyme 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

CCR5 and CXCR4 antagonistsVicriviroc (Schering):

Oct, 2005 discontinued Phase II trial due to therapeutic failure in some pts

Aplaviroc (GlaxoSmithKline): Oct, 2005 Phase III trials halted due to hepatotoxicity

Pfizer still has a compound in trials

Anti-viral drugs

Anti-herpes virus agents• Acyclovir / Valacyclovir• Famciclovir / Penciclovir • Ganciclovir / Cidofovir • Foscarnet • Trifluridine / Idoxuridine / Vidarabine

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Anti-viral drugsMechanism of action of Acyclovir and

congeners : All drugs are phosphorylated by a viral

thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs.

The analog inhibits viral DNA-polymerase Only actively replicating viruses are inhibited Acyclovir is thus selectively activated in

cells infected with herpes virus. Uninfected cells do not phosphorylate acyclovir.

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Acyclovir FDA approved in 1982structural analog of deoxyguanosinemechanism of selective toxicity

phosphorylated by viral thymidine kinase (TK) preferential incorporation by viral DNA polymerase causes chain termination

~20% oral bioavailability (valacyclovir is 3-5X better)

penetrates CSFeffective in treating

◦ primary Herpes infections (genital, encephalitis, neonatal)

◦ chronic Herpes (does not cure but can reduce recurrence)

Acyclovirmechanism of action

Resistance to acyclovirchronic therapy with acyclovir, valacyclovir,

famciclovirmutations in viral TK gene

◦alter affinity for drug or just completely inactivate the gene

viral DNA polymerase mutations◦reduce recognition of phosphorylated

drug as substrate for DNA synthesis

Ganciclovirfor CMV, varicella zoster (chicken

pox/shingles)similar to acyclovir6-9% oral bioavailabilitypenetrates CSFmore active than acyclovir against CMVtoxicity: bone marrow suppression, CNS

(headaches, convulsion, psychosis)◦some toxic effects seen in about 40% of pts

Foscarnetbinds to pyrophosphate site of viral

polymerase (also RTase)100 fold greater selective inhibitor or viral

versus human polymerasepoor oral bioavailabilitynephrotoxicity is high (~50%) but reversiblehypocalcemia and CNS toxicity is also

significant (25% pts)useful in acyclovir/ganciclovir resistant HSV

or CMV

 

Virus 

Diseases Drug(s) of choice

Alternative drugs

FLU A  

Influenza 

Amantadine Rimantadine

 

RSV Pneumonia,bronchiolitis

Ribavirin(aerosol)

  

HSV 

Genital herpes 

 Acyclovir 

Foscarnet 

   Keratitis

Conjunctivitis

 

Trifluridine IdoxuridineVidarabine

  

 

Encephalitis  

Acyclovir   

   Neonatal HSV

infection

 

Acyclovir 

Vidarabine   Herpes infections in

immuno- compromised host

 

Acyclovir 

Foscarnet37

  

VZV  

 

In normal host  

No therapy  

In immunocompro-mised host, or during pregnancy

 

Acyclovir 

Foscarnet

 

CMV 

Retinitis 

Ganciclovir 

Foscarnet

  

HIV

 

AIDSHIV antibody positive with CD4 count < 500/mm3

 

Zidovudine ± protease inhibitors

 

Didanosine,Stavudine

 

HBVHCV

 

Hepatitis B, C 

Interferons  

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