14. Viruses14. Viruses

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14. Viruses14. Viruses• Viruses are infective agents that are Viruses are infective agents that are

considerably smaller than bacteria. considerably smaller than bacteria. They are essentiallyThey are essentially packages, packages, known as virions, of chemicals that known as virions, of chemicals that invade host cells. invade host cells.

• However, viruses are notHowever, viruses are not independent and can only penetrate independent and can only penetrate a host cell that can a host cell that can satisfy the satisfy the specific needs specific needs of thatof that virus. virus.

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• The mode of penetration varies The mode of penetration varies considerably from virus to virus. Once considerably from virus to virus. Once inside the hostinside the host cell viruses cell viruses take over take over the metabolic machinery of the host the metabolic machinery of the host and use it to produce moreand use it to produce more virusesviruses. . Replication is often lethal to the host Replication is often lethal to the host cell, which may cell, which may undergo lysis to undergo lysis to release therelease the progeny of the virus.progeny of the virus.

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•However, in some cases the virus However, in some cases the virus may integrate into the hostmay integrate into the host chromosome chromosome and become and become dormant. The ability of viruses to dormant. The ability of viruses to reproduce means that they canreproduce means that they can be be regarded regarded as being on the as being on the borderline of being living borderline of being living organismsorganisms..

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14.1. Structure and 14.1. Structure and replicationreplication

•Viruses consist of a core of either Viruses consist of a core of either DNA or, as in the majority of cases, DNA or, as in the majority of cases, RNA RNA fully orfully or partially covered by a partially covered by a protein coating known as the protein coating known as the capsid. The capsid consists of a capsid. The capsid consists of a numbernumber of polypeptide molecules of polypeptide molecules known as capsomers (Fig.10.43).known as capsomers (Fig.10.43).

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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.

• The capsid that surrounds mostThe capsid that surrounds most viruses viruses consists of a number of different consists of a number of different capsomers although some viruses will capsomers although some viruses will havehave capsids that only contain one type capsids 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 determines around the nucleic acid that determines the overall shape of the virion.the overall shape of the virion.

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• In the majority ofIn the majority of viruses, the viruses, the capsomers form a layer or capsomers form a layer or several layers that completely several layers that completely surround the nucleicsurround the nucleic acids. acids. However, there are some viruses However, there are some viruses in which the capsomers form an in which the capsomers form an open-ended tubeopen-ended tube that holds the that holds the nucleic acids.nucleic acids.

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• In many viruses the capsid is coated In many viruses the capsid is coated with a with a protein-containing lipid bilayer protein-containing lipid bilayer membrane.membrane.

• These are known as enveloped These are known as enveloped viruses. Their lipid bilayers are often viruses. Their lipid bilayers are often derived from thederived from the plasma membrane plasma membrane of the host cell and are formed when of the host cell and are formed when the virus the virus leaves the host cell by aleaves the host cell by a process known as budding.process known as budding.

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• Budding is a mechanism by which a Budding is a mechanism by which a virus leaves a host cellvirus leaves a host cell without killing without killing that cell. that cell. It provides the virus with a It provides the virus with a membrane whose lipid components membrane whose lipid components areare identical to those of the host (Fig. identical to those of the host (Fig. 10.43). 10.43).

• This This allows the virus to penetrate allows the virus to penetrate new host cellsnew host cells without activating the without activating the host’s, immune systems.host’s, immune systems.

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• Viruses bind to host cells at specific Viruses bind to host cells at specific receptor sites on the host’s cell receptor sites on the host’s cell envelope.envelope.

• The binding sites on the virus are The binding sites on the virus are polypeptides in its capsid or polypeptides in its capsid or lipoprotein envelope.lipoprotein envelope. Once the virus Once the virus has bound to the receptor of the host has bound to the receptor of the host cell cell the virus–receptor complexthe virus–receptor complex is is transported into the cell by receptor-transported into the cell by receptor-mediated endocytosis.mediated endocytosis.

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• InIn the course of this process the protein the course of this process the protein capsid and any lipoprotein envelopes capsid and any lipoprotein envelopes may bemay be removed. removed.

• Once it has entered the host cell the Once it has entered the host cell the viral nucleic acid viral nucleic acid is able to use the is able to use the host’shost’s cellular machinery to synthesise cellular machinery to synthesise the nucleic acids and proteins required the nucleic acids and proteins required to replicateto replicate a number of new viruses a number of new viruses (Fig. 10.44).(Fig. 10.44).

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•A great deal of information is A great deal of information is availableavailable concerning the details of concerning the details of the mechanism of virus replication the mechanism of virus replication but this text will onlybut this text will only outline the outline the main points. For greater detail the main points. For greater detail the reader is referred to specialist reader is referred to specialist texts ontexts on virology.virology.

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14.2. Classification14.2. Classification

• RNA-viruses can be broadly classified RNA-viruses can be broadly classified into two general types, namely: RNA-into two general types, namely: RNA-viruses andviruses and RNA-retroviruses.RNA-retroviruses.

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• Figure 10.44 A schematic representation of the replication of Figure 10.44 A schematic representation of the replication of RNA-virusesRNA-viruses

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RNA-virusesRNA-viruses

•RNA-virus replication usually RNA-virus replication usually occurs entirely in the occurs entirely in the cytoplasm. The viral mRNA cytoplasm. The viral mRNA eithereither forms part of the RNA forms part of the RNA carried by the virion or is carried by the virion or is synthesised by an enzyme synthesised by an enzyme already presentalready present in the virion. in the virion.

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•This viral mRNA is used to This viral mRNA is used to produce the necessary viral produce the necessary viral proteins by translation using proteins by translation using the host cell’s ribosomes and the host cell’s ribosomes and enzyme systems.enzyme systems.

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•Some of the viral proteins areSome of the viral proteins are enzymes that are used to catalyse enzymes that are used to catalyse the reproduction of more viral the reproduction of more viral mRNA. The new viralmRNA. The new viral RNA and RNA and viral proteins are assembled into viral proteins are assembled into a number of new virions that are a number of new virions that are ultimatelyultimately released from the host released from the host cell by either lysis or buddingcell by either lysis or budding..

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RetrovirusesRetroviruses• Retroviruses Retroviruses synthesise viral DNA synthesise viral DNA

using their viral RNA as a using their viral RNA as a templatetemplate. .

• This process isThis process is catalysed by enzyme catalysed by enzyme systems known as systems known as reverse reverse transcriptasestranscriptases that form part of the that form part of the virion. Thevirion. The viral DNA is incorporated viral DNA is incorporated into the host genome to form a so-into the host genome to form a so-called called provirus.provirus.

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•Transcription ofTranscription of the provirus the provirus produces new ‘genomic’ viral produces new ‘genomic’ viral RNA and viral mRNA. The viral RNA and viral mRNA. The viral mRNA is used tomRNA is used to produce viral produce viral proteins, which together with the proteins, which together with the ‘genomic’ viral RNA are ‘genomic’ viral RNA are assembled into newassembled into new virions. virions.

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•These virions are released by These virions are released by budding , which in many budding , which in many cases does not kill the host cases does not kill the host cell. Retroviruses are cell. Retroviruses are responsible for some forms of responsible for some forms of cancer and AIDScancer and AIDS

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DNA-virusesDNA-viruses

• Most DNA-viruses enter the host cell’s Most DNA-viruses enter the host cell’s nucleus where formation of viral mRNA nucleus where formation of viral mRNA byby transcription from the viral DNA is transcription from the viral DNA is brought about by the host cell’s brought about by the host cell’s polymerases. This viralpolymerases. This viral mRNA is used mRNA is used to produce viral proteins by translation to produce viral proteins by translation using the host cell’s ribosomes andusing the host cell’s ribosomes and enzyme systems.enzyme systems.

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• Some of these proteins will be Some of these proteins will be enzymes that can catalyse the enzymes that can catalyse the synthesis ofsynthesis of more viral DNA. more viral DNA.

• This DNA and the viral proteins This DNA and the viral proteins synthesised in the host cell are synthesised in the host cell are assembledassembled into a number of new into a number of new virions that are ultimately released virions that are ultimately released from the host by either cell lysisfrom the host by either cell lysis or or buddingbudding

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14.3. Viral diseases14.3. Viral diseases

• Viral infection of host cells is a common Viral infection of host cells is a common occurrence. Most of the time this occurrence. Most of the time this infection doesinfection does not result in illness as not result in illness as the body’s immune system can usually the body’s immune system can usually deal with such viral invasiondeal with such viral invasion..

• When illness occurs it is often short When illness occurs it is often short lived and leads to long-term immunity.lived and leads to long-term immunity.

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• However, aHowever, a number of viral infections can lead to serious number of viral infections can lead to serious medical conditions (. Somemedical conditions (. Some viruses like HIV, the aetiological viruses like HIV, the aetiological agent of AIDS, are able to remain dormant in the host foragent of AIDS, are able to remain dormant in the host for a a number of years before becoming active, whilst others such as number of years before becoming active, whilst others such as herpes zoster (shingles)herpes zoster (shingles) can give rise to recurrent bouts of the can give rise to recurrent bouts of the illness. Both chemotherapy and preventativeillness. Both chemotherapy and preventative

• vaccination are used to treat vaccination are used to treat patients. The latter is the main patients. The latter is the main clinical approach since it hasclinical approach since it has

• been difficult to design drugs that only target the virus. been difficult to design drugs that only target the virus. However, a number of antiviralHowever, a number of antiviral

• drugs have been developed and are in clinical use.drugs have been developed and are in clinical use.

• AIDSAIDS

• AIDSAIDS

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• Both chemotherapy and preventativeBoth chemotherapy and preventative vaccination are used to treat vaccination are used to treat patients. The latter is the main patients. The latter is the main clinical approach since it hasclinical approach since it has been been difficult to design drugs that only difficult to design drugs that only target the virus. However, a number target the virus. However, a number of antiviralof antiviral drugs have been drugs have been developed and are in clinical use.developed and are in clinical use.

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AIDSAIDS

• AIDS is a disease that progressively AIDS is a disease that progressively destroys the human immune system. destroys the human immune system. It is caused by theIt is caused by the human human immunodeficiency virus (HIV), which immunodeficiency virus (HIV), which is a retrovirus. This virus is a retrovirus. This virus enters and enters and destroysdestroys human T4 lymphocyte cellshuman T4 lymphocyte cells. . These cells are a vital part of the These cells are a vital part of the human immune system.human immune system.

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•Their destruction reduces the Their destruction reduces the body’s resistance to other body’s resistance to other infectious diseases, such asinfectious diseases, such as pneumonia, and some rare forms pneumonia, and some rare forms of cancer.of cancer.

•..

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• The entry of the virus into the body The entry of the virus into the body usually causes an initial period of usually causes an initial period of acute ill health with the patient acute ill health with the patient suffering from headaches, fevers and suffering from headaches, fevers and rashes, amongst other symptoms.rashes, amongst other symptoms.

• This is followed by a period of This is followed by a period of relatively good healthy where the relatively good healthy where the virus replicates in the lymph nodes.virus replicates in the lymph nodes.

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• This relatively healthy period This relatively healthy period normally lasts a number of years normally lasts a number of years before fullblownbefore fullblown

• AIDS appears. Full-blown AIDS is AIDS appears. Full-blown AIDS is characterised by a wide variety of characterised 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 a a mixture of antiviral agents is usedmixture of antiviral agents is used

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14.4. Antiviral drugs14.4. Antiviral drugs

• It has been found that viruses utiliIt has been found that viruses utilizze e a number of virus-specific enzymes a number of virus-specific enzymes during replication.during replication.

• These enzymes and the processes These enzymes and the processes they control are significantly different they control are significantly different from those of thefrom those of the host cell host cell to make to make them a useful target for medicinal them a useful target for medicinal chemistschemists..

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•Consequently, antiviral drugsConsequently, antiviral drugs normally act by normally act by ::

• inhibiting viral nucleic acid inhibiting viral nucleic acid synthesis, synthesis,

• inhibiting inhibiting attachment to andattachment to and penetration of the host cell penetration of the host cell oror

• inhibiting viral protein synthesis.inhibiting viral protein synthesis.

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Nucleic acid synthesis Nucleic acid synthesis inhibitorsinhibitors• Nucleic acid synthesis inhibitors usually Nucleic acid synthesis inhibitors usually

act by inhibiting act by inhibiting the polymerases or the polymerases or reversereverse transcriptases required for transcriptases required for nucleic acid chain formationnucleic acid chain formation. .

• However, because they are usuallyHowever, because they are usually analogues of the purine and pyrimidine analogues 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 the incorporated into the growing nucleic acid chaingrowing nucleic acid chain..

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• In this case their general mode of In this case their general mode of actionaction frequently involves conversion frequently involves conversion to the cto the corresponding 5-triphosphate orresponding 5-triphosphate by the host cell’sby the host cell’s cellular kinasescellular kinases. .

• This conversion may also involve This conversion may also involve specific viral enzymes in the initialspecific viral enzymes in the initial monophosphorylation step.monophosphorylation step.

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• These triphosphate drug derivatives These triphosphate drug derivatives are incorporated into theare incorporated into the nucleic acid nucleic acid chain chain where they terminate its where they terminate its formationformation. Termination occurs because . Termination occurs because the drugthe drug residues do not have the residues do not have the 3-3-hydroxy group necessary for the hydroxy group necessary for the phosphate ester phosphate ester formationformation required for required for further growth of the nucleic acid further growth of the nucleic acid chain. chain.

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•This effectively inhibits the This effectively inhibits the polymerases and polymerases and ttranscriptases ranscriptases that catalythat catalyzze the growth of the e the growth of the nucleic acid (Fig. 10.45).nucleic acid (Fig. 10.45).

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AciclovirAciclovir• Aciclovir was the first effective Aciclovir was the first effective

antiviral drug. It is effective against a antiviral drug. It is effective against a number ofnumber of herpes viruses, notably herpes viruses, notably simplex, varicella-zoster (shingles), simplex, varicella-zoster (shingles), varicella (chickenpox) andvaricella (chickenpox) and Epstein–Epstein–Barr virus (glandular fever). Barr virus (glandular fever).

• It may be administered orally and by It may be administered orally and by intravenousintravenous injection as well as injection as well as topically. topically. Orally administered doses Orally administered doses have a low bioavailabilityhave a low bioavailability..

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• The action of aciclovir is more The action of aciclovir is more effective in virus-infected host cells effective in virus-infected host cells because the because the viralviral thymidine kinase is thymidine kinase is a more efficient catalyst for the a more efficient catalyst for the monophosphorylation of aciclovir monophosphorylation of aciclovir thanthan the thymidine kinases of the the thymidine kinases of the host cell.host cell.

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• This leads to an increase in the This leads to an increase in the concentration of theconcentration of the aciclovir aciclovir triphosphate, triphosphate, which has 100-fold which has 100-fold greater affinity for viral DNA greater affinity for viral DNA polymerase thanpolymerase than human DNA human DNA polymerase. polymerase.

• As a result, it preferentially As a result, it preferentially competitively inhibits viral DNAcompetitively inhibits viral DNA polymerase and so prevents the virus polymerase and so prevents the virus from replicating.from replicating.

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• However, resistance has beenHowever, resistance has been reported due to changes in the viral reported due to changes in the viral mRNA responsible for the production mRNA responsible for the production of the viralof the viral thymidine kinase. thymidine kinase.

• Aciclovir also acts by terminating Aciclovir also acts by terminating chain formation. chain formation. The aciclovir–DNAThe aciclovir–DNA complex complex formed by the drug also formed by the drug also irreversibly inhibits DNA polymerase.irreversibly inhibits DNA polymerase.

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VidarabineVidarabine

• Vidarabine is active against herpes Vidarabine is active against herpes simplex and herpes varicella-zoster.simplex and herpes varicella-zoster.

• However, the drug does give rise to However, the drug does give rise to nausea, vomiting, tremors, dizziness nausea, vomiting, tremors, dizziness and seizures. Inand seizures. In addition it has been addition it has been reported to be reported to be mutagenic, mutagenic, teratogenic and carcinogenic in teratogenic and carcinogenic in animal studiesanimal studies..

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• Vidarabine is administered by Vidarabine is administered by intravenous infusion and topical intravenous infusion and topical application. It has a half-lifeapplication. It has a half-life of about of about one hour, the drug being rapidly one hour, the drug being rapidly deaminated to arabinofuranosyl deaminated to arabinofuranosyl hypoxanthine (ara-HX) hypoxanthine (ara-HX) by adenosine by adenosine deaminase.deaminase.

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• This enzyme is found in the serum and red This enzyme is found in the serum and red blood cells. Ara-HX, which also exhibits a blood cells. Ara-HX, which also exhibits a weak antiviral action, has a half-life of weak antiviral action, has a half-life of about 3.5 hours.about 3.5 hours.

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Zidovudine (AZT)Zidovudine (AZT)• Zidovudine was originally synthesised Zidovudine was originally synthesised

in 1964 as an analogue ofin 1964 as an analogue of thymine by thymine by J. Horwitz as a potential antileukaemia J. Horwitz as a potential antileukaemia drug. drug.

• It was found to be unsuitable for useIt was found to be unsuitable for use in in 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 against it was active against Friend leukaemia virusFriend leukaemia virus, a retrovirus., a retrovirus.

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•However, the identification in However, the identification in 19831983 of the retrovirus HIVas the of the retrovirus HIVas the source of AIDS resulted in the source of AIDS resulted in the virologist M. St Clair setting up avirologist M. St Clair setting up a screening programme for drugs screening programme for drugs that could attack HIVthat could attack HIV

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• Fourteen compounds were selected Fourteen compounds were selected and screened against Friend leukaemia and screened against Friend leukaemia virus and a second retrovirus called virus and a second retrovirus called Harvey sarcoma virus. Harvey sarcoma virus.

• This screen led to the discovery of This screen led to the discovery of zidovudine (AZT), which was rapidly zidovudine (AZT), which was rapidly developed into clinical use on selected developed into clinical use on selected patients in 1986patients in 1986..

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•AZT is converted by the action of AZT is converted by the action of cellular thymidine kinase to the cellular thymidine kinase to the 5-triphosphate5-triphosphate. .

•ThisThis inhibits the enzyme reverse inhibits the enzyme reverse transcriptase in the retrovirus, transcriptase in the retrovirus, which effectively prevents itwhich effectively prevents it from from forming the viral DNA necessary forming the viral DNA necessary for viral replicationfor viral replication..

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• The incorporation of AZT intoThe incorporation of AZT into the the nucleic acid chain also results in nucleic acid chain also results in chain termination because chain termination because the the presence of the 3-azidepresence of the 3-azide group group prevents the reaction of the chain prevents the reaction of the chain with the 5-triphosphate with the 5-triphosphate of the next of the next nucleotidenucleotide waiting to join the chain waiting to join the chain (Fig. 10.45).(Fig. 10.45).

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•AZT is also active against AZT is also active against mammalian DNAmammalian DNA polymerase and polymerase and although its affinity for this although its affinity for this enzyme is about enzyme is about 100-fold less 100-fold less this action isthis action is thought to be the thought to be the cause of some of its unwanted cause of some of its unwanted side effects.side effects.

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• Zidovudine is active against the Zidovudine is active against the retroviruses (see section 10.14.2) retroviruses (see section 10.14.2) that cause AIDSthat cause AIDS (HIV virus) and (HIV virus) and certain types of leukaemia. certain types of leukaemia.

• It also inhibits cellular a-DNA It also inhibits cellular a-DNA polymerase butpolymerase but only at only at cconcentrations in excess of oncentrations in excess of 100-fold 100-fold greater greater than those needed to treat than those needed to treat the viralthe viral infection.infection.

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• The drug may be administered orally or The drug may be administered orally or by intravenous infusion. by intravenous infusion. TheThe bioavailability from oral administration bioavailability 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 it However, 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, depression anaemia, fever, headaches, depression and otherand other unwanted effects.unwanted effects.

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ResistanceResistance

•Resistance increases with time. Resistance increases with time. This is known to be due to This is known to be due to the the virusvirus developing mutations’developing mutations’ which result in changes in the which result in changes in the amino acid sequences in the amino acid sequences in the reversereverse transcriptase.transcriptase.

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DidanosineDidanosine

• Didanosine is used to treat some Didanosine is used to treat some AZT-resistant strains of HIV. It is also AZT-resistant strains of HIV. It is also used inused in combination with AZT to combination with AZT to treat HIV. Didanosine is administered treat HIV. Didanosine is administered orally in dosage forms thatorally in dosage forms that contain contain antacid buffers to prevent conversion antacid buffers to prevent conversion by the stomach acids to by the stomach acids to hypoxanthinehypoxanthine

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• However, in spite of the use of However, in spite of the use of buffers the bioavailability from oral buffers the bioavailability from oral administration isadministration is low. low.

• The drug can cause nausea, The drug can cause nausea, abdominal pain and peripheral abdominal pain and peripheral neuropathy, amongst otherneuropathy, amongst other symptoms. symptoms. Drug resistance occurs Drug resistance occurs after prolonged use.after prolonged use.

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• Didanosine is converted by viral and Didanosine is converted by viral and cellular kinases to the monophosphate cellular kinases to the monophosphate and then toand then to the triphosphatethe triphosphate. .

• In this form it inhibits reverse In this form it inhibits reverse transcriptase and in addition itstranscriptase and in addition its incorporation into the DNA chain incorporation into the DNA chain terminates the chain because terminates the chain because the drug the drug has no 3-hydroxyhas no 3-hydroxy group (Fig. 10.45group (Fig. 10.45).).

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Host cell penetration inhibitorsHost cell penetration inhibitors

• The principal drugs that act in this The principal drugs that act in this manner are amantadine and manner are amantadine and rimantadine (Fig. 10.46).rimantadine (Fig. 10.46).

• Both amantadine and rimantadine Both amantadine and rimantadine are also used to treat Parkinson’s are also used to treat Parkinson’s disease. However, theirdisease. However, their mode of mode of action in this disease is different from action in this disease is different from their action as antiviral agents.their action as antiviral agents.

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Amantadine Amantadine hydrochloridehydrochloride

•Amantadine hydrochloride is Amantadine hydrochloride is effective against influenza Aeffective against influenza A virus virus but is not effective against the but is not effective against the influenza B virus. When used as a influenza B virus. When used as a prophylactic, it isprophylactic, it is believed to give believed to give up to 80 per cent protection up to 80 per cent protection against influenza A virus infectionsagainst influenza A virus infections

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•The drugThe drug acts acts by blocking an ion by blocking an ion channel in the virus membrane channel in the virus membrane formed by the viral proteinformed by the viral protein M2. M2. This isThis is believed believed to inhibit the to inhibit the disassembly of the core of the disassembly of the core of the virion and its penetration of the virion and its penetration of the host host (see(see section 10.14.1).section 10.14.1).

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• Amantadine hydrochloride has a good Amantadine hydrochloride has a good bioavailability on oral administration, bioavailability on oral administration, beingbeing readily absorbed and distributed readily 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 in However, its use can result in depression, dizziness, insomnia anddepression, dizziness, insomnia and gastrointestinal disturbances, amongst gastrointestinal disturbances, amongst other unwanted side effects.other unwanted side effects.

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Rimantadine Rimantadine hydrochloridehydrochloride

•Rimantadine hydrochloride is an Rimantadine hydrochloride is an analogue of amantadineanalogue of amantadine hydrochloride. hydrochloride.

• It It is more effective against is more effective against influenza A virus influenza A virus than amantadine. than amantadine. Its mode ofIts mode of action is probably action is probably similar to that of amantadine.similar to that of amantadine.

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•The drug is readily absorbed whenThe drug is readily absorbed when administered orally but undergoes administered orally but undergoes extensive first-pass metabolism. extensive first-pass metabolism. However, in spite ofHowever, in spite of this, its this, its elimination half-life is double that elimination half-life is double that of amantadine. Furthermore, CNS of amantadine. Furthermore, CNS side effects areside effects are significantly significantly reduced.reduced.

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Inhibitors of viral protein Inhibitors of viral protein synthesissynthesis

• The principal compounds that act as The principal compounds that act as inhibitors of protein synthesis are the inhibitors of protein synthesis are the interferons.interferons.

• These compounds are members of a These compounds are members of a naturally occurring family of naturally occurring family of glycoprotein hormonesglycoprotein hormones (RMM 20 (RMM 20 000–160 000), which are produced 000–160 000), which are produced by nearly all types of eukaryotic cell.by nearly all types of eukaryotic cell.

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• Three general classes of interferons Three general classes of interferons are known are known to occur naturally in to occur naturally in mammals, namelymammals, namely:: the the αα-interferons -interferons produced by leucocytes, produced by leucocytes, ββ-interferons -interferons produced by fibroblasts andproduced by fibroblasts and γ-γ-interferons interferons produced by T produced by T lymphocyteslymphocytes. At least twenty . At least twenty αα-, two -, two ββ- - and two and two γγ-interferons-interferons have been have been identifiedidentified

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• Interferons form part of the human Interferons form part of the human immune system. immune system. It is believed that It is believed that the presence ofthe presence of virions, bacteria and virions, bacteria and other antigens in the body switches other antigens in the body switches on the mRNA that controls theon the mRNA that controls the production and release of interferon. production and release of interferon.

• This release stimulates other cells to This release stimulates other cells to produce andproduce and release more interferon.release more interferon.

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• Interferons are thought to act by Interferons are thought to act by initiating the initiating the production in theproduction in the cell of proteins that protect the cell of proteins that protect the cells from viral attackcells from viral attack. .

•The main action of these The main action of these proteinsproteins takes the form of takes the form of inhibiting the synthesis of viral inhibiting the synthesis of viral mRNA and viral protein mRNA and viral protein synthesis. synthesis.

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•a- Interferons also enhance a- Interferons also enhance the activity of killer T cells the activity of killer T cells associated with the immune associated with the immune system. (see section 14.5.5).system. (see section 14.5.5).

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•The main action of these proteins The main action of these proteins takes the form of takes the form of inhibiting the inhibiting the synthesis of viral mRNA and viral synthesis of viral mRNA and viral protein synthesisprotein synthesis. .

•αα- Interferons also - Interferons also enhance the enhance the activity of killer T cells activity of killer T cells associated associated with the immune system.with the immune system.

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•A number of a-interferons have A number of a-interferons have been manufactured andbeen manufactured and proven proven to be reasonably effective to be reasonably effective against a number of viruses and against a number of viruses and cancers. cancers.

• Interferons areInterferons are usually given by usually given by intravenous, intramuscular or intravenous, intramuscular or subcutaneous injection.subcutaneous injection.

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• However, theirHowever, their administration can administration can cause adverse effects, such as cause adverse effects, such as headaches, fevers and bone marrowheadaches, fevers and bone marrow depression, that are dose related.depression, that are dose related.

• The formation and release of The formation and release of interferon by viral and other interferon by viral and other pathological stimulation haspathological stimulation has resulted resulted in a search for chemical inducers of in a search for chemical inducers of endogenous interferon.endogenous interferon.

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•Administration of aAdministration of a wide range of wide range of compounds has resulted in the compounds has resulted in the induction of interferon production. induction of interferon production. However,However, no clinically useful no clinically useful compounds have been found for compounds have been found for humans’ although tilorone is humans’ although tilorone is effectiveeffective in inducing interferon in inducing interferon in in mice.mice.

prof. azaprof. aza