Viruses are smaller than bacteria and can only replicate inside host cells. They penetrate cells through various modes of entry and hijack the host's machinery to produce more viruses. This often kills the host cell. Viruses may also integrate dormantly into the host's genome. While not considered living organisms, their ability to reproduce makes them borderline living things. Viruses consist of genetic material surrounded by a protein capsid, and some have an outer envelope. They reproduce by taking over the host cell to produce more viral components, which are then assembled and released to infect new cells. Antiviral drugs target virus-specific enzymes to inhibit viral replication.

1. 14. Viruses14. Viruses
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2. 14. Viruses14. Viruses
• Viruses are infective agents that areViruses are infective agents that are
considerably smaller than bacteria.considerably smaller than bacteria.
They are essentiallyThey are essentially packages, known aspackages, known as
virions, of chemicals that invade hostvirions, of chemicals that invade host
cells.cells.
• However, viruses are notHowever, viruses are not independentindependent
and can only penetrate a host cell thatand can only penetrate a host cell that
cancan satisfy the specific needssatisfy the specific needs of thatof that
virus.virus.
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3. • The mode of penetration variesThe mode of penetration varies
considerably from virus to virus. Onceconsiderably from virus to virus. Once
inside the hostinside the host cell virusescell viruses take overtake over
the metabolic machinery of the host andthe metabolic machinery of the host and
use it to produce moreuse it to produce more virusesviruses..
Replication is often lethal to the hostReplication is often lethal to the host
cell, which maycell, which may undergo lysis to releaseundergo lysis to release
thethe progeny of the virus.progeny of the virus.
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4. • However, in some cases the virusHowever, in some cases the virus
may integrate into the hostmay integrate into the host
chromosomechromosome and become dormant.and become dormant.
The ability of viruses to reproduceThe ability of viruses to reproduce
means that they canmeans that they can be regardedbe regarded asas
being on the borderline of beingbeing on the borderline of being
living organismsliving organisms..
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5. 14.1. Structure and replication14.1. Structure and replication
• Viruses consist of a core of eitherViruses consist of a core of either
DNA or, as in the majority ofDNA or, as in the majority of
cases, RNAcases, RNA fully orfully or partiallypartially
covered by a protein coating knowncovered by a protein coating known
as theas the capsid. The capsid consistscapsid. The capsid consists
of a numberof a number of polypeptideof polypeptide
molecules known as capsomersmolecules known as capsomers
(Fig.10.43).(Fig.10.43).
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6. prof. azaprof. aza
Figure 10.37. (a) Schematic representations of the
structure of a virus (a) without a lipoprotein
envelope (naked virus) and (b) with a lipoprotein
envelope.

7. • The capsid that surrounds mostThe capsid that surrounds most virusesviruses
consists of a number of differentconsists of a number of different
capsomers although some viruses willcapsomers although some viruses will
havehave capsids that only contain one typecapsids that only contain one type
of capsomer.of capsomer.
• It is the arrangement of the capsomersIt is the arrangement of the capsomers
around the nucleic acid that determinesaround the nucleic acid that determines
the overall shape of the virion.the overall shape of the virion.
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8. • In the majority ofIn the majority of viruses, theviruses, the
capsomers form a layer or severalcapsomers form a layer or several
layers that completely surround thelayers that completely surround the
nucleicnucleic acids. However, there areacids. However, there are
some viruses in which thesome viruses in which the
capsomers form an open-endedcapsomers form an open-ended
tubetube that holds the nucleic acids.that holds the nucleic acids.
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9. • In many viruses the capsid is coatedIn many viruses the capsid is coated
with awith a protein-containing lipid bilayerprotein-containing lipid bilayer
membrane.membrane.
• These are known as enveloped viruses.These are known as enveloped viruses.
Their lipid bilayers are oftenTheir lipid bilayers are often derivedderived
from thefrom the plasma membrane of the hostplasma membrane of the host
cell and are formed when the viruscell and are formed when the virus
leaves the host cell by aleaves the host cell by a process knownprocess known
as budding.as budding.
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10. • Budding is a mechanism by which a virusBudding is a mechanism by which a virus
leaves a host cellleaves a host cell without killing thatwithout killing that
cell.cell. It provides the virus with aIt provides the virus with a
membrane whose lipid components aremembrane whose lipid components are
identical to those of the host (Fig.identical to those of the host (Fig.
10.43).10.43).
• ThisThis allows the virus to penetrate newallows the virus to penetrate new
host cellshost cells without activating the host’s,without activating the host’s,
immune systems.immune systems.
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11. • Viruses bind to host cells at specificViruses bind to host cells at specific
receptor sites on the host’s cellreceptor sites on the host’s cell
envelope.envelope.
• The binding sites on the virus areThe binding sites on the virus are
polypeptides in its capsid or lipoproteinpolypeptides in its capsid or lipoprotein
envelope.envelope. Once the virus has bound toOnce the virus has bound to
the receptor of the host cellthe receptor of the host cell the virus–the virus–
receptor complexreceptor complex is transported intois transported into
the cell by receptor-mediatedthe cell by receptor-mediated
endocytosis.endocytosis.
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12. • InIn the course of this process thethe course of this process the
protein capsid and any lipoproteinprotein capsid and any lipoprotein
envelopes may beenvelopes may be removed.removed.
• Once it has entered the host cell theOnce it has entered the host cell the
viral nucleic acidviral nucleic acid is able to use theis able to use the
host’shost’s cellular machinery to synthesisecellular machinery to synthesise
the nucleic acids and proteins requiredthe nucleic acids and proteins required
to replicateto replicate a number of new virusesa number of new viruses
(Fig. 10.44).(Fig. 10.44).
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13. • A great deal of information isA great deal of information is
availableavailable concerning the details ofconcerning the details of
the mechanism of virus replicationthe mechanism of virus replication
but this text will onlybut this text will only outline theoutline the
main points. For greater detail themain points. For greater detail the
reader is referred to specialistreader is referred to specialist
texts ontexts on virology.virology.
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14. 14.2. Classification14.2. Classification
• RNA-viruses can be broadly classified intoRNA-viruses can be broadly classified into
two general types, namely: RNA-virusestwo general types, namely: RNA-viruses
andand RNA-retroviruses.RNA-retroviruses.
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15. • Figure 10.44 A schematic representationFigure 10.44 A schematic representation
of the replication of RNA-virusesof the replication of RNA-virusesprof. azaprof. aza

16. RNA-virusesRNA-viruses
• RNA-virus replication usuallyRNA-virus replication usually
occurs entirely in the cytoplasm.occurs entirely in the cytoplasm.
The viral mRNA eitherThe viral mRNA either formsforms
part of the RNA carried by thepart of the RNA carried by the
virion or is synthesised by anvirion or is synthesised by an
enzyme already presentenzyme already present in thein the
virion.virion.
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17. • This viral mRNA is used toThis viral mRNA is used to
produce the necessary viralproduce the necessary viral
proteins by translation using theproteins by translation using the
host cell’s ribosomes andhost cell’s ribosomes and
enzyme systems.enzyme systems.
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18. • Some of the viral proteins areSome of the viral proteins are
enzymes that are used to catalyseenzymes that are used to catalyse
the reproduction of more viralthe reproduction of more viral
mRNA. The new viralmRNA. The new viral RNA and viralRNA and viral
proteins are assembled into aproteins are assembled into a
number of new virions that arenumber of new virions that are
ultimatelyultimately released from the hostreleased from the host
cell by either lysis or buddingcell by either lysis or budding..
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19. RetrovirusesRetroviruses
• RetrovirusesRetroviruses synthesise viral DNAsynthesise viral DNA
using their viral RNA as a templateusing their viral RNA as a template..
• This process isThis process is catalysed by enzymecatalysed by enzyme
systems known assystems known as reversereverse
transcriptasestranscriptases that form part of thethat form part of the
virion. Thevirion. The viral DNA is incorporatedviral DNA is incorporated
into the host genome to form a so-into the host genome to form a so-
calledcalled provirus.provirus.
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20. • Transcription ofTranscription of the provirusthe provirus
produces new ‘genomic’ viral RNAproduces new ‘genomic’ viral RNA
and viral mRNA. The viral mRNA isand viral mRNA. The viral mRNA is
used toused to produce viral proteins,produce viral proteins,
which together with the ‘genomic’which together with the ‘genomic’
viral RNA are assembled into newviral RNA are assembled into new
virions.virions.
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21. • These virions are released byThese virions are released by
budding , which in many casesbudding , which in many cases
does not kill the host cell.does not kill the host cell.
Retroviruses are responsibleRetroviruses are responsible
for some forms of cancer andfor some forms of cancer and
AIDSAIDS
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22. DNA-virusesDNA-viruses
• Most DNA-viruses enter the host cell’sMost DNA-viruses enter the host cell’s
nucleus where formation of viral mRNAnucleus where formation of viral mRNA
byby transcription from the viral DNA istranscription from the viral DNA is
brought about by the host cell’sbrought about by the host cell’s
polymerases. This viralpolymerases. This viral mRNA is used tomRNA is used to
produce viral proteins by translationproduce viral proteins by translation
using the host cell’s ribosomes andusing the host cell’s ribosomes and
enzyme systems.enzyme systems.
prof. azaprof. aza

23. • Some of these proteins will be enzymesSome of these proteins will be enzymes
that can catalyse the synthesis ofthat can catalyse the synthesis of moremore
viral DNA.viral DNA.
• This DNA and the viral proteinsThis DNA and the viral proteins
synthesised in the host cell aresynthesised in the host cell are
assembledassembled into a number of new virionsinto a number of new virions
that are ultimately released from thethat are ultimately released from the
host by either cell lysishost by either cell lysis or buddingor budding
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24. 14.3. Viral diseases14.3. Viral diseases
• Viral infection of host cells is a commonViral infection of host cells is a common
occurrence. Most of the time thisoccurrence. Most of the time this
infection doesinfection does not result in illness asnot result in illness as
the body’s immune system can usuallythe body’s immune system can usually
deal with such viral invasiondeal with such viral invasion..
• When illness occurs it is often shortWhen illness occurs it is often short
lived and leads to long-term immunity.lived and leads to long-term immunity.
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25. • However, aHowever, a number of viral infectionsnumber of viral infections
can lead to serious medical conditions (.can lead to serious medical conditions (.
SomeSome viruses like HIV, the aetiologicalviruses like HIV, the aetiological
agent of AIDS, are able to remainagent of AIDS, are able to remain
dormant in the host fordormant in the host for a number ofa number of
years before becoming active, whilstyears before becoming active, whilst
others such as herpes zoster (shingles)others such as herpes zoster (shingles)
can give rise to recurrent bouts of thecan give rise to recurrent bouts of the
illness. Both chemotherapy andillness. Both chemotherapy and
preventativepreventative prof. azaprof. aza

26. • Both chemotherapy and preventativeBoth chemotherapy and preventative
vaccination are used to treat patients.vaccination are used to treat patients.
The latter is the main clinical approachThe latter is the main clinical approach
since it hassince it has been difficult to designbeen difficult to design
drugs that only target the virus.drugs that only target the virus.
However, a number of antiviralHowever, a number of antiviral drugsdrugs
have been developed and are in clinicalhave been developed and are in clinical
use.use.
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27. prof. azaprof. aza

28. AIDSAIDS
• AIDS is a disease that progressivelyAIDS is a disease that progressively
destroys the human immune system. Itdestroys the human immune system. It
is caused by theis caused by the humanhuman
immunodeficiency virus (HIV), which is aimmunodeficiency virus (HIV), which is a
retrovirus. This virusretrovirus. This virus enters andenters and
destroysdestroys human T4 lymphocyte cellshuman T4 lymphocyte cells..
These cells are a vital part of theThese cells are a vital part of the
human immune system.human immune system.
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29. • Their destruction reduces theTheir destruction reduces the
body’s resistance to otherbody’s resistance to other
infectious diseases, such asinfectious diseases, such as
pneumonia, and some rare forms ofpneumonia, and some rare forms of
cancer.cancer.
• ..
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30. • The entry of the virus into the bodyThe entry of the virus into the body
usually causes an initial period of acuteusually causes an initial period of acute
ill health with the patient sufferingill health with the patient suffering
from headaches, fevers and rashes,from headaches, fevers and rashes,
amongst other symptoms.amongst other symptoms.
• This is followed by a period of relativelyThis is followed by a period of relatively
good healthy where the virus replicatesgood healthy where the virus replicates
in the lymph nodes.in the lymph nodes.
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31. • This relatively healthy period normallyThis relatively healthy period normally
lasts a number of years beforelasts a number of years before
fullblownfullblown
• AIDS appears. Full-blown AIDS isAIDS appears. Full-blown AIDS is
characterised by a wide variety ofcharacterised by a wide variety of
diseases suchdiseases such as bacterial infections,as bacterial infections,
neurological diseases and cancers.neurological diseases and cancers.
Treatment is more effective whenTreatment is more effective when aa
mixture of antiviral agents is usedmixture of antiviral agents is used
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32. 14.4. Antiviral drugs14.4. Antiviral drugs
• It has been found that viruses utiliIt has been found that viruses utilizze ae a
number of virus-specific enzymes duringnumber of virus-specific enzymes during
replication.replication.
• These enzymes and the processes theyThese enzymes and the processes they
control are significantly different fromcontrol are significantly different from
those of thethose of the host cellhost cell to make them ato make them a
useful target for medicinal chemistsuseful target for medicinal chemists..
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33. • Consequently, antiviral drugsConsequently, antiviral drugs
normally act bynormally act by ::
• inhibiting viral nucleic acidinhibiting viral nucleic acid
synthesis,synthesis,
• inhibitinginhibiting attachment to andattachment to and
penetration of the host cellpenetration of the host cell oror
• inhibiting viral protein synthesis.inhibiting viral protein synthesis.
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34. Nucleic acid synthesis inhibitorsNucleic acid synthesis inhibitors
• Nucleic acid synthesis inhibitors usuallyNucleic acid synthesis inhibitors usually
act by inhibitingact by inhibiting the polymerases orthe polymerases or
reversereverse transcriptases required fortranscriptases required for
nucleic acid chain formationnucleic acid chain formation..
• However, because they are usuallyHowever, because they are usually
analogues of the purine and pyrimidineanalogues of the purine and pyrimidine
bases found in the viral nucleic acids,bases found in the viral nucleic acids,
they are oftenthey are often incorporated into theincorporated into the
growing nucleic acid chaingrowing nucleic acid chain..
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35. • In this case their general mode ofIn this case their general mode of
actionaction frequently involves conversion tofrequently involves conversion to
the cthe corresponding 5-triphosphate byorresponding 5-triphosphate by
the host cell’sthe host cell’s cellular kinasescellular kinases..
• This conversion may also involve specificThis conversion may also involve specific
viral enzymes in the initialviral enzymes in the initial
monophosphorylation step.monophosphorylation step.
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36. • These triphosphate drug derivatives areThese triphosphate drug derivatives are
incorporated into theincorporated into the nucleic acid chainnucleic acid chain
where they terminate its formationwhere they terminate its formation..
Termination occurs because the drugTermination occurs because the drug
residues do not have theresidues do not have the 3-hydroxy3-hydroxy
group necessary for the phosphategroup necessary for the phosphate
esterester formationformation required for furtherrequired for further
growth of the nucleic acid chain.growth of the nucleic acid chain.
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37. • This effectively inhibits theThis effectively inhibits the
polymerases andpolymerases and ttranscriptasesranscriptases
that catalythat catalyzze the growth of thee the growth of the
nucleic acid (Fig. 10.45).nucleic acid (Fig. 10.45).
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38. prof. azaprof. aza

39. AciclovirAciclovir
• Aciclovir was the first effectiveAciclovir was the first effective
antiviral drug. It is effective against aantiviral drug. It is effective against a
number ofnumber of herpes viruses, notablyherpes viruses, notably
simplex, varicella-zoster (shingles),simplex, varicella-zoster (shingles),
varicella (chickenpox) andvaricella (chickenpox) and Epstein–BarrEpstein–Barr
virus (glandular fever).virus (glandular fever).
• It may be administered orally and byIt may be administered orally and by
intravenousintravenous injection as well as topically.injection as well as topically.
Orally administered doses have a lowOrally administered doses have a low
bioavailabilitybioavailability..
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40. • The action of aciclovir is more effectiveThe action of aciclovir is more effective
in virus-infected host cells because thein virus-infected host cells because the
viralviral thymidine kinase is a morethymidine kinase is a more
efficient catalyst for theefficient catalyst for the
monophosphorylation of aciclovirmonophosphorylation of aciclovir thanthan
the thymidine kinases of the host cell.the thymidine kinases of the host cell.
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41. • This leads to an increase in theThis leads to an increase in the
concentration of theconcentration of the acicloviraciclovir
triphosphate,triphosphate, which has 100-foldwhich has 100-fold
greater affinity for viral DNAgreater affinity for viral DNA
polymerase thanpolymerase than human DNAhuman DNA
polymerase.polymerase.
• As a result, it preferentiallyAs a result, it preferentially
competitively inhibits viral DNAcompetitively inhibits viral DNA
polymerase and so prevents the viruspolymerase and so prevents the virus
from replicating.from replicating.
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42. • However, resistance has beenHowever, resistance has been reportedreported
due to changes in the viral mRNAdue to changes in the viral mRNA
responsible for the production of theresponsible for the production of the
viralviral thymidine kinase.thymidine kinase.
• Aciclovir also acts by terminating chainAciclovir also acts by terminating chain
formation.formation. The aciclovir–DNAThe aciclovir–DNA complexcomplex
formed by the drug also irreversiblyformed by the drug also irreversibly
inhibits DNA polymerase.inhibits DNA polymerase.
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43. VidarabineVidarabine
• Vidarabine is active against herpesVidarabine is active against herpes
simplex and herpes varicella-zoster.simplex and herpes varicella-zoster.
• However, the drug does give rise toHowever, the drug does give rise to
nausea, vomiting, tremors, dizziness andnausea, vomiting, tremors, dizziness and
seizures. Inseizures. In addition it has beenaddition it has been
reported to bereported to be mutagenic, teratogenicmutagenic, teratogenic
and carcinogenic in animal studiesand carcinogenic in animal studies..
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44. • Vidarabine is administered byVidarabine is administered by
intravenous infusion and topicalintravenous infusion and topical
application. It has a half-lifeapplication. It has a half-life of aboutof about
one hour, the drug being rapidlyone hour, the drug being rapidly
deaminated to arabinofuranosyldeaminated to arabinofuranosyl
hypoxanthine (ara-HX)hypoxanthine (ara-HX) by adenosineby adenosine
deaminase.deaminase.
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45. • This enzyme is found in the serum and redThis enzyme is found in the serum and red
blood cells. Ara-HX, which also exhibits ablood cells. Ara-HX, which also exhibits a
weak antiviral action, has a half-life of aboutweak antiviral action, has a half-life of about
3.5 hours.3.5 hours.
prof. azaprof. aza

46. prof. azaprof. aza

47. Zidovudine (AZT)Zidovudine (AZT)
• Zidovudine was originally synthesised inZidovudine was originally synthesised in
1964 as an analogue of1964 as an analogue of thymine by J.thymine by J.
Horwitz as a potential antileukaemiaHorwitz as a potential antileukaemia
drug.drug.
• It was found to be unsuitable for useIt was found to be unsuitable for use inin
this role and for 20 years was ignored,this role and for 20 years was ignored,
even though in 1974even though in 1974 W. Osterag et al.W. Osterag et al.
reported thatreported that it was active againstit was active against
Friend leukaemia virusFriend leukaemia virus, a retrovirus., a retrovirus.
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48. • However, the identification in 1983However, the identification in 1983
of the retrovirus HIVas the sourceof the retrovirus HIVas the source
of AIDS resulted in the virologistof AIDS resulted in the virologist
M. St Clair setting up aM. St Clair setting up a screeningscreening
programme for drugs that couldprogramme for drugs that could
attack HIVattack HIV
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49. • Fourteen compounds were selected andFourteen compounds were selected and
screened against Friend leukaemia virusscreened against Friend leukaemia virus
and a second retrovirus called Harveyand a second retrovirus called Harvey
sarcoma virus.sarcoma virus.
• This screen led to the discovery ofThis screen led to the discovery of
zidovudine (AZT), which was rapidlyzidovudine (AZT), which was rapidly
developed into clinical use on selecteddeveloped into clinical use on selected
patients in 1986patients in 1986..
prof. azaprof. aza

50. prof. azaprof. aza

51. • AZT is converted by the action ofAZT is converted by the action of
cellular thymidine kinase to the 5-cellular thymidine kinase to the 5-
triphosphatetriphosphate..
• ThisThis inhibits the enzyme reverseinhibits the enzyme reverse
transcriptase in the retrovirus,transcriptase in the retrovirus,
which effectively prevents itwhich effectively prevents it fromfrom
forming the viral DNA necessaryforming the viral DNA necessary
for viral replicationfor viral replication..
prof. azaprof. aza

52. • The incorporation of AZT intoThe incorporation of AZT into thethe
nucleic acid chain also results in chainnucleic acid chain also results in chain
termination becausetermination because the presence ofthe presence of
the 3-azidethe 3-azide group prevents the reactiongroup prevents the reaction
of the chain with the 5-triphosphateof the chain with the 5-triphosphate ofof
the next nucleotidethe next nucleotide waiting to join thewaiting to join the
chain (Fig. 10.45).chain (Fig. 10.45).
prof. azaprof. aza

53. • AZT is also active againstAZT is also active against
mammalian DNAmammalian DNA polymerase andpolymerase and
although its affinity for thisalthough its affinity for this
enzyme is aboutenzyme is about 100-fold less100-fold less thisthis
action isaction is thought to be the cause ofthought to be the cause of
some of its unwanted side effects.some of its unwanted side effects.
prof. azaprof. aza

54. • Zidovudine is active against theZidovudine is active against the
retroviruses (see section 10.14.2) thatretroviruses (see section 10.14.2) that
cause AIDScause AIDS (HIV virus) and certain(HIV virus) and certain
types of leukaemia.types of leukaemia.
• It also inhibits cellular a-DNAIt also inhibits cellular a-DNA
polymerase butpolymerase but only atonly at cconcentrations inoncentrations in
excess ofexcess of 100-fold greater100-fold greater than thosethan those
needed to treat the viralneeded to treat the viral infection.infection.
prof. azaprof. aza

55. • The drug may be administered orally orThe drug may be administered orally or
by intravenous infusion.by intravenous infusion. TheThe
bioavailability from oral administrationbioavailability from oral administration
is goodis good, the drug being distributed into, the drug being distributed into
most bodymost body fluids and tissues.fluids and tissues.
• However, when used to treat AIDS itHowever, when used to treat AIDS it
has given rise to gastrointestinalhas given rise to gastrointestinal
disorders, skin rashes, insomnia,disorders, skin rashes, insomnia,
anaemia, fever, headaches, depressionanaemia, fever, headaches, depression
and otherand other unwanted effects.unwanted effects.
prof. azaprof. aza

56. ResistanceResistance
• Resistance increases with time.Resistance increases with time.
This is known to be due toThis is known to be due to the virusthe virus
developing mutations’developing mutations’ which resultwhich result
in changes in the amino acidin changes in the amino acid
sequences in the reversesequences in the reverse
transcriptase.transcriptase.
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57. DidanosineDidanosine
• Didanosine is used to treat some AZT-Didanosine is used to treat some AZT-
resistant strains of HIV. It is also usedresistant strains of HIV. It is also used
inin combination with AZT to treat HIV.combination with AZT to treat HIV.
Didanosine is administered orally inDidanosine is administered orally in
dosage forms thatdosage forms that containcontain antacidantacid
buffers to prevent conversion by thebuffers to prevent conversion by the
stomach acids to hypoxanthinestomach acids to hypoxanthine
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58. • However, in spite of the use of buffersHowever, in spite of the use of buffers
the bioavailability from oralthe bioavailability from oral
administration isadministration is low.low.
• The drug can cause nausea, abdominalThe drug can cause nausea, abdominal
pain and peripheral neuropathy, amongstpain and peripheral neuropathy, amongst
otherother symptoms.symptoms. Drug resistance occursDrug resistance occurs
after prolonged use.after prolonged use.
prof. azaprof. aza

59. prof. azaprof. aza

60. • Didanosine is converted by viral andDidanosine is converted by viral and
cellular kinases to the monophosphatecellular kinases to the monophosphate
and then toand then to the triphosphatethe triphosphate..
• In this form it inhibits reverseIn this form it inhibits reverse
transcriptase and in addition itstranscriptase and in addition its
incorporation into the DNA chainincorporation into the DNA chain
terminates the chain becauseterminates the chain because the drugthe drug
has no 3-hydroxyhas no 3-hydroxy group (Fig. 10.45group (Fig. 10.45).).
prof. azaprof. aza

61. Host cell penetration inhibitorsHost cell penetration inhibitors
• The principal drugs that act in thisThe principal drugs that act in this
manner are amantadine and rimantadinemanner are amantadine and rimantadine
(Fig. 10.46).(Fig. 10.46).
• Both amantadine and rimantadine areBoth amantadine and rimantadine are
also used to treat Parkinson’s disease.also used to treat Parkinson’s disease.
However, theirHowever, their mode of action in thismode of action in this
disease is different from their actiondisease is different from their action
as antiviral agents.as antiviral agents.
prof. azaprof. aza

62. prof. azaprof. aza

63. Amantadine hydrochlorideAmantadine hydrochloride
• Amantadine hydrochloride isAmantadine hydrochloride is
effective against influenza Aeffective against influenza A virusvirus
but is not effective against thebut is not effective against the
influenza B virus. When used as ainfluenza B virus. When used as a
prophylactic, it isprophylactic, it is believed to givebelieved to give
up to 80 per cent protectionup to 80 per cent protection
against influenza A virus infectionsagainst influenza A virus infections
prof. azaprof. aza

64. prof. azaprof. aza

65. • The drugThe drug actsacts by blocking an ionby blocking an ion
channel in the virus membranechannel in the virus membrane
formed by the viral proteinformed by the viral protein M2.M2.
This isThis is believedbelieved to inhibit theto inhibit the
disassembly of the core of thedisassembly of the core of the
virion and its penetration of thevirion and its penetration of the
hosthost (see(see section 10.14.1).section 10.14.1).
prof. azaprof. aza

66. • Amantadine hydrochloride has a goodAmantadine hydrochloride has a good
bioavailability on oral administration,bioavailability on oral administration,
beingbeing readily absorbed and distributedreadily absorbed and distributed
to most body fluids and tissues.to most body fluids and tissues.
• Its elimination time isIts elimination time is 12–18 hours.12–18 hours.
However, its use can result inHowever, its use can result in
depression, dizziness, insomnia anddepression, dizziness, insomnia and
gastrointestinal disturbances, amongstgastrointestinal disturbances, amongst
other unwanted side effects.other unwanted side effects.
prof. azaprof. aza

67. Rimantadine hydrochlorideRimantadine hydrochloride
• Rimantadine hydrochloride is anRimantadine hydrochloride is an
analogue of amantadineanalogue of amantadine
hydrochloride.hydrochloride.
• ItIt is more effective againstis more effective against
influenza A virusinfluenza A virus than amantadine.than amantadine.
Its mode ofIts mode of action is probablyaction is probably
similar to that of amantadine.similar to that of amantadine.
prof. azaprof. aza

68. • The drug is readily absorbed whenThe drug is readily absorbed when
administered orally but undergoesadministered orally but undergoes
extensive first-pass metabolism.extensive first-pass metabolism.
However, in spite ofHowever, in spite of this, itsthis, its
elimination half-life is double thatelimination half-life is double that
of amantadine. Furthermore, CNSof amantadine. Furthermore, CNS
side effects areside effects are significantlysignificantly
reduced.reduced.
prof. azaprof. aza

69. Inhibitors of viral proteinInhibitors of viral protein
synthesissynthesis
• The principal compounds that act asThe principal compounds that act as
inhibitors of protein synthesis are theinhibitors of protein synthesis are the
interferons.interferons.
• These compounds are members of aThese compounds are members of a
naturally occurring family ofnaturally occurring family of
glycoprotein hormonesglycoprotein hormones (RMM 20 000–(RMM 20 000–
160 000), which are produced by nearly160 000), which are produced by nearly
all types of eukaryotic cell.all types of eukaryotic cell.
prof. azaprof. aza

70. • Three general classes of interferonsThree general classes of interferons
are knownare known to occur naturally into occur naturally in
mammals, namelymammals, namely:: thethe αα-interferons-interferons
produced by leucocytes,produced by leucocytes, ββ-interferons-interferons
produced by fibroblasts andproduced by fibroblasts and γ-γ-
interferonsinterferons produced by T lymphocytesproduced by T lymphocytes..
At least twentyAt least twenty αα-, two-, two ββ- and two- and two γγ--
interferonsinterferons have been identifiedhave been identified
prof. azaprof. aza

71. • Interferons form part of the humanInterferons form part of the human
immune system.immune system. It is believed that theIt is believed that the
presence ofpresence of virions, bacteria and othervirions, bacteria and other
antigens in the body switches on theantigens in the body switches on the
mRNA that controls themRNA that controls the production andproduction and
release of interferon.release of interferon.
• This release stimulates other cells toThis release stimulates other cells to
produce andproduce and release more interferon.release more interferon.
prof. azaprof. aza

72. • Interferons are thought to act byInterferons are thought to act by
initiating theinitiating the production in theproduction in the cellcell
of proteins that protect the cellsof proteins that protect the cells
from viral attackfrom viral attack..
• The main action of these proteinsThe main action of these proteins
takes the form oftakes the form of inhibiting theinhibiting the
synthesis of viral mRNA and viralsynthesis of viral mRNA and viral
protein synthesis.protein synthesis.
prof. azaprof. aza

73. • a- Interferons also enhance thea- Interferons also enhance the
activity of killer T cellsactivity of killer T cells
associated with the immuneassociated with the immune
system. (see section 14.5.5).system. (see section 14.5.5).
prof. azaprof. aza

74. • The main action of these proteinsThe main action of these proteins
takes the form oftakes the form of inhibiting theinhibiting the
synthesis of viral mRNA and viralsynthesis of viral mRNA and viral
protein synthesisprotein synthesis..
• αα- Interferons also- Interferons also enhance theenhance the
activity of killer T cellsactivity of killer T cells associatedassociated
with the immune system.with the immune system.
prof. azaprof. aza

75. • A number of a-interferons haveA number of a-interferons have
been manufactured andbeen manufactured and proven toproven to
be reasonably effective against abe reasonably effective against a
number of viruses and cancers.number of viruses and cancers.
• Interferons areInterferons are usually given byusually given by
intravenous, intramuscular orintravenous, intramuscular or
subcutaneous injection.subcutaneous injection.
prof. azaprof. aza

76. • However, theirHowever, their administration can causeadministration can cause
adverse effects, such as headaches,adverse effects, such as headaches,
fevers and bone marrowfevers and bone marrow depression,depression,
that are dose related.that are dose related.
• The formation and release of interferonThe formation and release of interferon
by viral and other pathologicalby viral and other pathological
stimulation hasstimulation has resultedresulted in a search forin a search for
chemical inducers of endogenouschemical inducers of endogenous
interferon.interferon.
prof. azaprof. aza

77. • Administration of aAdministration of a wide range ofwide range of
compounds has resulted in thecompounds has resulted in the
induction of interferon production.induction of interferon production.
However,However, no clinically usefulno clinically useful
compounds have been found forcompounds have been found for
humans’ although tilorone ishumans’ although tilorone is
effectiveeffective in inducing interferonin inducing interferon inin
mice.mice.
prof. azaprof. aza