Download Anti-viral drugs - Lectures For UG-5

Antivirals
Lect 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:
induced by viral infection,
ά (made in leukocytes)
IL1, IL2, TNF
β (made in fibroblasts)
γ (made in T cells) activated T cells produce g interferon
to modulate the immune response
Cytokine signaling pathway
Multiple Pathways of Interferon Action
Clinical use of Interferon

alpha 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
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

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 Agents
1) Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
2) Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
3)Protease inhibitors
Antivirals: Purine Nucleosides
Agent
Antiviral Activity
guanines
acyclovir
HSV 1 & 2, VZV
ganciclovir (DHPG)
CMV retinitis and systemic
CMV infection
ribavirin (RTCD)
Influenza types A and B,
RSV, LV, HV
adenosines
didanosine (ddl)
HIV
vidarabine (Ara-A)
HSV, herpes zoster
Antivirals: Pyrimidine Nucleosides
Agent
Antiviral Activity
cytosines
lamivudine (3TC)
zalcitabine (ddC)
HIV
HIV
thymine
idoxuridine (IDU)
stavudine (d4T)
trifluridine
zidovudine (AZT)
HSV
HIV
HSV
HIV
Zidovudine (AZT) RTase inhibitor
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

Zidovudine (AZT) RTase inhibitor

mechanism
◦ selective reverse transcriptase inhibitor
Mechanism of selective toxicity of AZT
DNA
synthesis
AZT concentration (uM)
Zidovudine

mechanism
◦ selective reverse transcriptase inhibitor

pharmacokinetics:
◦ 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 zidovudine
 resistance develops quickly: selects for
met184val mutation in RTase
 lamivudine + zidovudine combination
dramatically slows resistance development

NNRTIs
(non-nucleoside
reverse transcriptase
inhibitors)
Nevirapine
Delavirdine
Efavirenz
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
 Nevirapine- prevents transmission of HIV from mother to
newborn when given at onset of labor and to the neonate
at delivery

Protease Inhibitors
The 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 antagonists
Vicriviroc (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 drugs
Mechanism of action of Acyclovir and congeners :

All drugs are phosphorylated by a viral thymidinekinase, 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 1982
structural analog of deoxyguanosine
mechanism 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 CSF
effective in treating
◦ primary Herpes infections (genital, encephalitis, neonatal)
◦ chronic Herpes (does not cure but can reduce recurrence)
Acyclovir
mechanism of action
Resistance to acyclovir
chronic therapy with acyclovir, valacyclovir,
famciclovir
 mutations 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
Ganciclovir
for CMV, varicella zoster (chicken
pox/shingles)
 similar to acyclovir
 6-9% oral bioavailability
 penetrates CSF
 more active than acyclovir against CMV
 toxicity: bone marrow suppression, CNS
(headaches, convulsion, psychosis)

◦ some toxic effects seen in about 40% of pts
Foscarnet






binds to pyrophosphate site of viral polymerase
(also RTase)
100 fold greater selective inhibitor or viral versus
human polymerase
poor oral bioavailability
nephrotoxicity is high (~50%) but reversible
hypocalcemia and CNS toxicity is also significant
(25% pts)
useful in acyclovir/ganciclovir resistant HSV or
CMV
Virus
FLU A
Diseases
Drug(s) of
choice
Alternative
drugs
Rimantadine
Influenza
Amantadine
RSV
Pneumonia,
bronchiolitis
Ribavirin
(aerosol)
HSV
Genital herpes
Acyclovir
Foscarnet
Keratitis
Conjunctivitis
Trifluridine
Idoxuridine
Vidarabine
Encephalitis
Acyclovir
Neonatal HSV
infection
Acyclovir
Vidarabine
Herpes infections in
immunocompromised host
Acyclovir
Foscarnet
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VZV
CMV
HIV
HBV
HCV
In normal host
No therapy
In immunocompro-mised
host, or during pregnancy
Acyclovir
Foscarnet
Retinitis
Ganciclovir
Foscarnet
AIDS
HIV antibody positive
with CD4 count <
500/mm3
Zidovudine ±
protease inhibitors
Didanosine,
Stavudine
Hepatitis B, C
Interferons
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