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Antiviral Drugs
Drug: Vidarabine Acyclovir (ancyclovir and Valcyte ) &valganciclovir' Viruses: $erpesviruses $erpes simplex &$SV' *ytomegalovirus &*+V' Chemical Type: %ucleoside analogue %ucleoside analogue %ucleoside analogue Target: Virus polymerase Virus polymerase Virus polymerase &needs virus U,-. kinase /or activation'

%ucleoside-analog reverse transcriptase inhibitors &%012': A31 &3idovudine'! %ucleoside dd2 &4idanosine'! dd* 0etroviruses &$2V' analogue &3alcitabine'! d51 &Stavudine'! 61* &,amivudine' %on-nucleoside reverse transcriptase inhibitors &%%012': %evirapine! 4elavirdine 7rotease 2nhibitors: Sa8uinavir! 0itonavir! 2ndinavir! %el/inavir 0ibavirin 0etroviruses &$2V' %ucleoside analogue 7eptide analogue

0everse transcriptase

0everse transcriptase

$2V 9road spectrum: $*V! $SV! measles! mumps! ,assa /ever

$2V protease

1ria:ole 0%A mutagen carboxamide 1ricyclic amine +atrix protein / haemagglutinin

Amantadine / 0imantadine 2n/luen:a A strains 0elen:a and 1ami/lu 7leconaril 2nter/erons

2n/luen:a strains A %euraminic %euraminidase and 9 acid mimetic 2nhibitor 7icornaviruses $epatitis 9 and * Small cyclic 7rotein 9locks attachment and uncoating *ell de/ense proteins activated

$istorically! the discovery o/ antiviral drugs has been largely /ortuitous. Spurred on by success with antibiotics! drug companies launched huge blind-screening programmes - with relatively little success. ,ead compounds were modi/ied by chemists in an attempt to improve bioactivity. Solubility! stability! availability and activity are all important Scientists would like to think rationale drug design could be accomplished i.e determine the structure o/ your target in a complex with a known inhibitor. Use this and other biochemical knowledge to ;theoretically design; a better inhibitor. +ake it and test it. $owever in recent years combinatorial chemistry has become /ashionable.1his uses robotic techni8ues to make enormous numbers o/ di//erent compounds /rom a limited number o/ subunits. 1he nature o/ the subunits can vary widely. *onsider a library o/ <" compounds. =ne reaction will give <"" di//erent compounds. <-<....<-<"> -<... -<"> .....> <"-<....<"-<". 1wo reactions will give <""". 1en reactions will give one hundred thousand million? 1he individual compounds! or pools o/ compunds are then assayed /or bioactivity. Any active compounds identi/ied can be used as a lead compound. 1he key to success in drug development is specificity! e.g. 7aul @rlichAs ;magic bullets;. Any stage o/ virus replication can be a target /or a drug! but drug must be more toxic to virus than to the host.

CHEMOTHERAPUTIC INDEX =
Dose of drug which inhibits virus replication / Dose of drug which is toxic to host 1he smaller this value o/ this number the better! i.e. several orders o/ magnitude di//erence is re8uired /or a really sa/e drug. +odern technology allows deliberate design o/ drugs! but to do this! need to ;know your enemy;:

+olecular biology - understanding viral replication and producing speci/ic targets /or inhibition *omputer aided design &*.A.4.'

Strategies for antiviral thera !

*ommonly used therapuetically. ASA7 a/ter in/ection or clinical signs o/ in/ection. 7rophylactic use occasionally. Any o/ the stages o/ viral replication can be a target /or antiviral intervention. 1he only re8uirements are: <. 1hat the process targeted be essential /or virus replication. . 1hat the theraputic agent is active against the virus while having ;acceptable toxicity; to the host organism

Atta"h#ent
1his phase o/ replication can be inhibited in two ways: a' Using agents which mimic the V.A.7. and bind to the cellular receptor! e.g:

anti-receptor antibodies V.A.7. anti-idiotypic antibodies natural ligands o/ the receptor! e.g. epidermal growth /actor/Vaccinia virus synthetic ligands! e.g. synthetic peptides resembling the receptor-binding domain o/ the V.A.7. itsel/.

b' Agents which mimic the receptor and bind to the V.A.7:

anti-V.A.7. antibodies &a natural component o/ the antibody response to virus in/ection/vaccination' receptor anti-idiotypic antibodies extraneous receptor! e.g. rs*45/$2V synthetic receptor mimics! e.g. sialic acid derivatives/in/luen:a virus.

Bhile the above are promising lines o/ experimental research! there are considerable problems with clinical use o/ any o/ these substances. 1he cost o/ synthetic peptides is prohibitive when the amounts re8uired /or clinically e//ective whole body doses> the generation o/ anti-idiotypic antibodies is a complex! poorly understood process> the pharmacokinetics o/ many o/ these synthetic compounds is very poor.

Penetration $ Un"oating
2t is di//icult to speci/ically target these stages o/ the li/e cycle as relatively little is known about them. Uncoating in particular is largely mediated by cellular en:ymes! although like penetration! is o/ten in/luenced by one or more virus proteins. Pleconaril is a broad spectrum anti-picorna virus agent. 2t is orally bioavailable and reduces peak viral titres by more than --C> symptoms are improved. 2t is a small cyclic drug which binds to a canyon pore o/ the virus. 2n doing so it blocks attachment and uncoating o/ the viral particle

Amantadine and rimantadine are active against in/luen:a A viruses. 1he action o/ these closely related agents is complex and incompletely understood! but they are believed to block cellular membrane ion channels.

1he target /or both drugs is the matrix protein &+ '. 4rug-treated cells are unable to lower the p$ o/ the endosomal compartment &a /unction normally controlled by the + gene product'! a process which is essential to induce con/ormational changes in the $A protein to permit membrane /usion.

%eno#e Re li"ation
+any viruses have evolved their own speci/ic en:ymatic mechanisms to pre/erentially replicate virus nucleic acids at the expense o/ cellular molecules. 1here is o/ten su//icient speci/icity in virus polymerases to provide a target /or a speci/ic antiviral agent! and this method has produced the maDority o/ the speci/ic antiviral drugs currently in use. 1he maDority o/ these drugs /unction as polymerase substrate &i.e. nucleoside/nucleotide' analogues. 1he toxicity o/ these drugs varies considerably /rom some which are well tolerated &e.g. acyclovir' to others which are highly toxic &e.g. 2dU/1E1/A31'. 1here is a serious problem with the pharmacokinetics o/ these nucleoside analogues! e.g. typically short serum hal/ lives o/ <-5h. %ucleoside analogues are in /act pro drugs! since they need to be phosphorylated be/ore becoming e//ective. 1his is the key to their selectivity:

Acyclovir is phosphorylated by $SV tk "" times more e//iciently than by cellular en:ymes. 1he cell 4%A polymerase is less sensitive to it than the viral 4%A polymerase. !ancyclovir is <" times more e//ective against *+V than acyclovir since it is speci/ically phosphorylated by a *+V-encoded kinase encoded by gene UL97 :

+ore recently! a series o/ other nucleoside analogues derived /rom these drugs and active against herpesviruses have been developed:

"ucleoside analogues active against #$V:

%ene E& ression

Virus gene expression is less amenable to intervention than genome replication! since viruses are much more dependent on the cellular machinery /or transcription! m0%A splicing! cytoplasmic export and translation than /or replication.

Asse#'l! $ Maturation $ Release

As stated above! /or the maDority o/ viruses! these processes are poorly understood. 1wo drugs with anti in/luen:a activity are available! %elen&a taken as an aerosol and Tamiflu taken as a pill. 1he latter is active against both A and 9 strains. 9oth /unction as neuraminidase inhibitors and prevent the release o/ budded viruses /rom the cell. 9ecause they act late in the li/e cycle o/ the virus it is hoped that problems with resistance emergence will be minimised. 1ami/lu is reported to be -"C e//ective as a prophylactic agent.

Other antiviral (rugs)

Thera ! of HI* Infe"tion)

Several distinct classes o/ drugs are now used to treat $2V in/ection: 1. "ucleoside Analog %everse Transcriptase $nhibitors '"%T$( . 1hese drugs inhibit viral 0%A-dependent 4%A polymerase &reverse transcriptase' and are incorporated into viral 4%A &they are chainterminating drugs'. o 3idovudine &A31 F 34V! 0etrovir' /irst approved in <-.G o 4idanosine &dd2! Videx' o 3alcitabine &dd*! $ivid' o Stavudine &d51! 3erit' o ,amivudine &61*! @pivir' 2. "on "ucleoside %everse Transcriptase $nhibitors '""%T$s( . 2n contrast to %012s! %%012s are not incorporated into viral 4%A> they inhibit $2V replication directly by binding non-competitively to reverse transcriptase. o %evirapine &Viramune' o 4elavirdine &0escriptor' 3. Protease $nhibitors. 1hese drugs are speci/ic /or the $2V-< protease and competitively inhibit the en:yme! preventing the maturation o/ virions capable o/ in/ecting other cells. o Sa8uinavir &2nvirase' /irst approved in <--# o 0itonavir &%orvir' o 2ndinavir &*rixivan' o %el/inavir &Viracept'

Pro'le#s
1oxicity. A31 causes anaemia! in /act its toxicity is such that it was originally reDected as an anti-tumour drug? 2nter/eron and acyclovir can cause severe nausia and vomiting. 7regnancy is an important contraindication because o/ possible teratogenic e//ects. )edscape Article: Update o/ Antiretroviral 1herapy /or $2V 2n/ection: ;Bith early diagnosis and optimum management! the li/e expectancy o/ the $2V-in/ected patient appears similar to that o/ patients with ... diabetes. Eor many patients today! $2V in/ection is becoming a chronic! more manageable condition.;

4etailed notes /or these documents can be /ound in *hapter H o/ 7rinciples o/ +olecular Virology.

$nstructors Version: 1he 5th edition contains new 5th edition contains new material on virus structure! material on virus structure! virus evolution! :oonoses! virus evolution! :oonoses! bushmeat! SA0S and bushmeat! SA0S and bioterrorism! *4-0=+ with bioterrorism! *4-0=+ with all E,AS$ animations! virtual the Standard Version content interactive tutorials and plus all the /igures /rom the experiments! sel/-assessment 8uestions! use/ul book in electronic /orm and a 7ower7oint slide online resources! along with the glossary! set with complete lecture notes to aid in course classi/ication o/ subcellular in/ectious agents and preparation. &Ama:on.co.uk' history o/ virology. &Ama:on.co.uk'
9ooks about antivirals

*tandard Version: 1he

9ooks about antibiotics

Update Box: News: Canada says warnings needed on bird flu drug Tamiflu (News-MedicalNet)
posted on December 01, 00! 0"#1!#1! am

Publications: ,atest 7ublications

Canadian $ealt$ aut$ority %ealt$ Canada $as re&uested t$at t$e manufacturer of t$e anti'iral drug Tamiflu place warnings((( )oenning * +cattergood ,nnounces -n'estment .pinion# )oenning * +cattergood initiates co'erage of %emisp$er/ )iop$arma, ()usiness 0ire 'ia 1a$oo2 3inance)
posted on December 04, 00! 05# !#00 pm

06+T C.N+%.%.C76N, 8a(----)oenning * +cattergood initiates co'erage of %emisp$er/ )iop$arma -nc( wit$ a Mar9et .utperfo((( )oenning * +cattergood ,nnounces -n'estment .pinion# )oenning * +cattergood -nitiates Co'erage of %emisp$er/ )iop$arma, (:edNo'a)
posted on December 04, 00! 10#1;#<" pm

)oenning * +cattergood initiates co'erage of %emisp$er/ )iop$arma -nc( (,M6=#%6)) wit$ a Mar9et .utperform rating and a ((( >anus s$ingles treatment produces

encouraging results (8$armaceutical )usiness :e'iew)

posted on December 0;, 00! 0 # 5#4" am

>anus 8$armaceuticals $as reported positi'e results from its study of topical ,:1+-01 cream for t$e treatment of patient((( ,C+ News +er'ice 0ee9ly 8ress8ac -- No'( ?, 00! (6ure9,lert2)
posted on December 04, 00! 0 #0<#; pm

%ere is t$e latest ,merican C$emical +ociety (,C+) News +er'ice 0ee9ly press pac9age (8ress8ac) wit$ reports selected fr((( ,atest %ews Search the BBB /or more in/ormation on Search Pub)ed /or all publications on this this topic topic

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