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InterIerons

By: Katy NassiI


iscovery oI InterIerons
1957
Isaacs and Lindenmann
id an experiment using chicken cell
cultures
Found a substance that interIered with
viral replication and was thereIore
named interIeron
Nagano and Kojima also
independently discovered this soluble
antiviral protein
hat are InterIerons?
Naturally occurring proteins and glycoproteins
Secreted by eukaryotic cells in response to viral
inIections, tumors, and other biological inducers
Produce clinical beneIits Ior disease states such
as hepatitis, various cancers, multiple sclerosis,
and many other diseases
Strucurally, they are part oI the helical cytokine
Iamily which are characterized by an amino acid
chain that is 145-166 amino acids long
nterferons are small proteins
released by macrophages,
lymphocytes, and tissue cells
infected with a virus.
When a tissue cell is infected by a
virus, it releases interferon.
nterferon will diffuse to the
surrounding cells. When it binds to
receptors on the surface of those
adjacent cells, they begin the
production of a protein that prevents
the synthesis of viral proteins. This
prevents the spread of the virus
throughout the body.
eneral Action oI
InterIerons
Three types oI interIerons: alpha,
beta and gamma.
Type I InterIerons
Type I: alpha and beta
Alpha interIerons are produced by leukocytes
Beta interIerons are produced by Iibroblasts
Both bind to interIeron cell receptors type 1 and both
encoded on chromosome 9
They have diIIerent binding aIIinities but similar
biological eIIects
Viral inIection is the stimulus Ior alpha and beta
expression
Used to mobilize our 1
st
line oI deIense against
invading organisms
Largest group and are secreted by almost all cell
types
The exact mechanism oI type I interIerons are
not Iully understood, but this is an idea oI
what happens:
Alpha and beta bind to heterodimeric receptor on cell
surIace.
Alpha receptor is made up oI at least 2 polypeptide chains:
IFNa-R1 and IFNa-R2
IFNa-R1 is involved in signal transduction
IFNa-R2 is the ligand-binding chain that also plays a role
in signal transduction
Ligation induces oligomerisation and initiation oI the
signal transduction pathway
This results in phosphorylation oI signal transductors and
activators oI transcription proteins, which translocate to the
nucleous as a trimeric complex, ISF-3.
ISF-3 activates transcription oI interIeron stimulated
genes, with many biological eIIects.
Type II InterIeron (gamma)
Bind to type 2 receptors and its genes are encoded on
chromosome 12
Initially believed that T helper cell type 1 lymphocytes,
cytotoxic lymphocytes and natural killer cells only produced
IFNg, now evidence that B cells, natural killer T cells and
proIessional antigen-presenting
cells secrete IFNg also.
amma production Iollows
activation with immune and
inIlammatory stimuli rather
than viral inIection.
This production is controlled
by cytokines secreted by
interleukin 12 and 18.
InterIeron amma Receptor
Composed oI two ligand binding IFNg-R1 chains
associated with two signal transducing IFNg-R2
chains
The IFNg-R2 chain is generally the limiting Iactor
in IFNg responsiveness, as the IFNg-R1 chain is
usually in excess.
The IFNg-R1 intracellular domain contains
binding spots Ior the Jak 1, latent cytosolic Iactor,
signal transducer and activator oI transcription
(Stat1)
IFNg only associates with IFNg-R2 when the
IFNg-R1 chain is present.
InterIeron amma Receptor and Signalling Pathway
Receptors are encoded by separate genes
(# and #, respectively) that
are located on diIIerent chromosomes.
As the ligand-binding (or -) chains interact
with IFN- they dimerise and become
associated with two signal-transducing
chains.
Receptor assembly leads to activation oI
the Janus kinases JAK1 and JAK2 and
phosphorylation oI a tyrosine residue on the
intracellular domain oI IFN-R1.
This leads to the recruitment and
phosphorylation oI STAT1, which Iorms
homodimers and translocates to the nucleus
to activate a range oI IFN--responsive
genes.
AIter this, the ligand-binding chains are
internalised and dissociate.
The chains are then recycled to the cell
surIace.
iIIerent InterIeron rugs
InterIerons are broken down into recombinant versions oI a speciIic interIeron
subtype and puriIied blends oI natural human interIeron.
Many oI these are in clinical use and are given intramuscularly or
subcutaneously
Recombinant Iorms oI alpha interIeron include:
Alpha-2a drug name RoIeron
Alpha-2b drug name Intron A
Alpha-n1 drug name ellIeron
Alpha-n3 drug name AlIeronN
Alpha-con1 drug name InIergen
Recombinant Iorms oI beta interIeron include:
Beta-1a drug name Avonex
Beta-1b drug name Betaseron
Recombinant Iorms oI gamma interIeron include:
amma-1b drug name Acimmune
Alpha InterIeron-2a (RoIeron A)
Protein chain that is 165 amino acids long
Produced using recombinant NA technology
Non-glycosylated protein
Short halI liIe, short terminal elimination oI halI
liIe, a large volume oI distribution, and a larger
reduction in renal clearance.
These problems were resolved by pegylating
alpha-2a resulting in peginterIeron alpha-2a that is
named Pegasys.
Pegylated InterIeron-2a
(Pegasys)
Background:
First developed by avis, Abuchowski and colleagues in the
1970s
In early 1990s PE attached to alpha-2a, but it lacked the
required proIile oI improving pharmacokinetics
Pegylation oI interIeron alpha-2b was achieved with the
addition oI a linear PE, designed to degrade to allow the Iull
potency oI the interIeron, while achieving a longer halI-liIe.
Pegasys is recombinant interIeron alpha-2a
that is covalently conjugated with bis-
monomethoxy polyethylene glycol (PE)
Structure:
CH3(OCH2CH2)n--OH
mPEOO2CCNH
mPEOO2CNH(CH2)4
O
PE moieties are inert, longchain amphiphilic
molecules that are produced by linking repeating
units oI ethylene oxide.
Can be linear or branched in their structure
Increasing the size with PE, the absorption and
liIe are prolongued and the clearance oI the IFN
is decreased.
oal oI pegylation is to decrease clearence,
retention oI biological activity, get a stable linkage
and enhance water solubility
Pegylation is achieved by
the covalent attachment oI
PE derivatives that utilize
amino groups oI lysines and
the N-terminus oI
polypeptide molecules as the
modiIication site
InterIeron Beta-2a (Avonex)
FA approval on May 17 1996 Ior Relapsing
Remitting MS
Clinical trials showed that it slowed MS
progression and had an extra beneIit oI slowing or
preventing the development oI MS-related brain
atropy.
The exact mechanism oI IFN beta activity in
treating MS is unknown, but studies have shown that
interlukin 10 levels in the cerebrospinal Iluid were
increased in patients
Structurally IFNb-2a is a 166 amino acid
glycoprotein.
Produced by recombinant NA technology using
genetically engineered mammalian cells which the
human beta gene has been introduced into
Amino acid sequence is the same as human beta
interIeron. They are both glycosylated at the
asparagines residue at position 80
Some side eIIects include:
Flu-like symptoms
Muscle aches
Chills
Combination Therapy with
Ribavirin
Many times interIerons and peginterIerons
are used in combination with Ribavirin
It is a purine nucleoside analogue with a
modiIied base and a -ribose sugar moiety
1
st
made in 1970 by rs. Joseph
itkowski and Roland Robins
It inhibits the replication oI a variety oI
RNA and NA viruses and is serves as an
immunomodulator to enhance type 1
cytokine production. This increases the
end oI treatment response and reduces
post-treatment relapse.
Mechanism is not well known, but there
are 4 proposed mechanisms
Conclusion
InterIerons have overlapping but diIIerent
biological activities
Their mechanisms oI action are not Iully
understood, thereIore there is a lot oI room Ior
Iuture growth within this Iield
InterIeron based strategies can possibly be Iurther
tailored to each individual patient according to
early response dynamics
Other immunomodulatiors that are being tested
include: Zadaxin and Ceplene
ReIerences
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463-472.
3. ecatris, Marios. 'Potential oI InterIeron-alIa in Solid Tumours. Biodrugs
16 (2002): 261-268.
4. oodsell, avid S. 'The Molecular Perspective: InterIerons The
Oncologist 6 (2001): 374-375.
5. Hertzog, Paul J. 'InterIeron-gamma: an overview oI signals, mechanisms
and Iunctions. Journal oI Leukocyte Biology 75 (2004): 163-179.
6. Lau, Johnson Y.N. 'Mechanism oI Action oI Ribavirin in the Combination
Treatment oI Chronic HVC InIection. Perspectives in Clinical Hepatology 35
(2002): 1002-1007.
7. Matthews, James S. 'PeginterIeron AlIa-2a: A Review oI Approval and
Investigational Uses. Clinical Therapeutics 26 (2004): 991-998.
8. Pedder, Simon C.J. 'Pegylation oI InterIeron AlIa: Structural and
Pharmacokinetic Properties. Seminars in Liver isease 23 (2003): 19-21.
9. Schreiber, regory H. 'InterIeron gamma. The Cytokine Handbook 4
(2003):567-569.
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