Antimicrobials - where next? A short history of antivirals Live and let die

49 Pages·2014·11.93 MB·English

BI
QUARIEMRALYG AZOINFTE H ES OCIEFTOYGR ENERMAICL ROBIOVLOOGLUYM3 1EM A2YO 04
-
Antimicrobialws heren ext?
A shorht istoroyf a ntivirals
-
Livea ndl etd ie biocideinst heh ome
Manipulatignegn esfo rn ewd rugs
Microbianla rcotics
Hostd efencpee ptides
Structrua lp athogenoimcs
Coldr ushfo rdrugs?
SGMHeadquarters Articles
MarlborougHho use,
WBaosoidnR,g estaodkRienoR ga GdS7, 1p AenGcers Antimicrobia-ls w heren ext?D avidJ ,P ayne 55
Tel.[phone] Antiviraldrug- sa shorth istoryo ft heirdiscoveryand
Fax0 11 BgBB5656
emaiml [email protected] developmenHt ,J.F ielda ndE .D e Clercq 6e
SGMWebsite Livea ndl et die PeferG ilberta ndA ndrewM cBain
http://www.sgm.ac.uk
Editor Newd rugsb ym anipulatinSg treptomycesgenes
DrGaviTn homas DavidH opwood 64
EditorialBoard
DrS ueA ssinder Microbianl arcoticsD eborahA . Rathbonea nd
DrP aulinHe andley NeilC.Bruce 66
ProfessorTonNya sh
Hostd efencep eptidesD eir dr e Devni e 70
ManagingEditor
JanetH urst Structur alp athogenomic sI a n Bou c he r ,J i m Br ann i g an,
PrcduetionEditor Ma rk Fogga nd Cl aud i a Schn i c k 74
lanA therton
Assistant Editor and Above:500 mgtablets (pp.5 8-O 1) whilstD eirdre
BookReviewManager oft hea ntibioticce ohalexin. 3iil[;?:l J::"JJ$f;iR:"'e'' sur arF eatur es
JaniceM eekings
JamesK ing-Holmes/
CThoenstreiab rueta iolwnsaysw elcomea nd ScienceP hotoL ibrary asa nti-infectivaeo ents SocietyN ews
(pp.70-72)
shouldb ea ddressetodt heE ditor Vol.31,Part2, FebruarCy ounciMl eeting 76
(c/o SGM Headquarters). May2(D4 Belieftsh atu sing AnnuaGl eneraMl eeting to
CLaosptyd Dataetesfo srr eceipot f copy Onlyafewyearasg o biocidetso raises tandards CouncilOfficers 76
atM arlborouoHho usea re. scientisitsh oughtt hey of hygienein b otht he StaffNews 76
aenerat coDV hads eeno ff infectious homea ndi ndustrym ay NewsofM embers 76
August2004issueM31a y diseasesb,u tt he microbes havec ontributetdo the SGM PrizeL ecturesa ndA wards 77
ANOovveemnsbee2mr0 e0n4(tiL ssR suUe3) 0 Auqust foughtb ackI.n t hisi ssue develoomenotf antmi i crobial Grants 79
Augus2t 004i ssue2 BJ une we exoloreth ec urrenst tate resistancaer ec halle noed Meetings 80
Novembe2r0 04i ssue2 7 Seot of playw itha ntimicrobials, byP eterG ilberat ndA idrew
Advertisements alongsidseo meo ther McBain( pp.6 2-63),T hey Gradline 82
Allenquirisehso ulbde s entto: interactionbse tween thinkt hatt he beneift sf ar SchoolZone 84
InaC oiks,H ardyA dvertising,
GranvilHleo use1,1 2B ermondseymicro-organismasn dd rugs. outweighth e risks, RegionaBl ioni formaticWs orkshop2s0 04 87
Street,LondonS3ETl X Mosta ntib acteriatlh erapy Them icrobiaml etabolism
rFeal0x2OO2703 737 788 165 47291 stilld eoendso nc lasseso f of narcoticd rugss ucha s HotofftheP ress 92
emaiiln a@h ardyadvertnigs .i co.ku antibioticdse velooe2dO heroina ndc ocaineis Reviews qR
Subscriptions 2OO4 yearsa go,b uti ncreasing coveredb vD eborah
NON-MEMBERS resistancme eansth atn ew RathboneanNde ilBruce Council 104
(Mui c sr $o8b i 5o I .o 0g0y) Toda y 950.00 typeso f drugsa ren eeded, (pp,6 6-68).T hesefi ndings Diary 111
MEN/BERS DavidP a:v-\ner ecounts areo fferings omei nterestingComment
Allm emberrse ceiveM icrobiology(pp,b b-5'i ) howd itterent. applications, Coldr ushf ordrugs?N ickRussell 112
Today.lna ddilionth eym ayt ake approacheasr er equired, InC ommenNt, ickR ussell
anyo ft heS ocietyj'so urnals. becausgee nomicsa,l though(p.1 1 2 ) pleadsfo rthe
MOredminbaeryrMsheSimpu bbesrcorit ion openingu pp ossibilities, uniouee nvironmeonft Other ltems
(inc,M i c r ob i o I o g y To d a y) cannoot rovidael lthe Antarcticato be orotected
c45.00( us$78.00) answers. f romb ioprospectowrsh o Letters 54
sMBic5ro.Obi(0oU lo5q$vJ1/G 6V0/. lJ0S 0E)M Despiteth e problems, seekt o exploitth e potential MicrobiologyAwarenCesasm paigSn cotland 88
JMMS45,00(U5$78.00) therei ss tilhl ooe.Informatioonft he residenpt sychrophiles.
Studenot rR etiredM ember gleanedfr omg enome Thesea rticlesa ppearin Microbiologinyt her egions- member'rse port
(cMin2ec0m.M. 0bi c 0(er uorb ssiio $h SI 3io pug 5 y b. 0Tso0 cd )ra ipy)tion tsoe dqeuteenrmciinncgesa t nrub cetu usreeodsf faedadtuitrieostnao na dlr ltehoeor erigso uflar SGGlMasSgyomwpVoisroiulomgVyoWluomrkes6Dh3oarpve ivdMiJea.wEr ivaaZnasm bon 9961
genep roductsT.h is
sM4ic0r.o0b0(i oul5o$o7v/5J.G00V) 'structuragle nomicsh' as Societya ctivities, ObituaryB:Ero wn VI
/JSEMCB5.0(0U S$1 6 0.00) manya pplicationinst he
JMM5,45.00(US$78.00) searchfo r newa ntimicrobials
Un dergra du a teo r Scho olM e m b er accordingto lanB oucher
MembershSipu bscripti(oinn c. andc olleagu es( pp.7 4-75).
Mi c r obio I o gyT odal)S 10 .00
DavidH opwoode xplains
CorporateM ember
MembershSipu bscripti(oinnc . hown ewa ntibioticfsro m
Mi c r obi o I o gy Toda y) 9350/ 500 Streptomycesm ayyetb e
USO fficeo f Publication: producebdy applying
Mi c r obio I o gyT oda y,c / o Mercury genetica ndc hemical
Airrf eighItn ternationLatdl 3, 65 technique(sp p.6 -65).
BlairR oadA, veneNl, JO7010, U SA.
Postmastesre: ndU Sa ddress Researchin toa ntiviraliss
correctiontso Mi crobiologTy oday makingg reatp rogress,
c/o thisa ddress. asH ughF ielda ndE rik
O 2004T heS ocietfyo rG eneral DeC lercod escribe The views expressed by contributors are not necessarily those of the
MicrobiologIyS;S N: 14 64-057O Society; norcan the claims of advertisers be guaranteed.
flenta htuer'Ceo fo thmement' ' 'l' i, i. u,.,,1. -' ,' :; :' ' ".,.1' j '' sE.H*l€Fk+ain-ldtoS sohc hairledtr h eeg caordnicnegtrh neso c fu Prrreonfets stsaoterosH f o vwetaerrdinary
Novembe2r0 03 1. , * 1,"., , , -t i. ,,; : ' ; ': :, ":t *t: '.ri tmimicers opbeionltoo ngOc yln,i neio cfat shlu ebp jreocbtslae tmthmse e uxsptb eentsheoe if n pcrree-aclsineidcal
iTsosudeao yf ,MCicorlHoinob wioalorgdy ,i- i ' 't','"'r 1"* ,,'I .,'l, i1 ., subjectsB, asick nowledgeis a lsol ackingo n manyoft he
exotics peciesin w hicht hem oderng raduatem ayw isht o
andG eoffreSv child .#;-1.tk n,o tet hatS GM isc ur rentlyc onside rin g howb esti t specializFe,o rthosew ishingto specializien m icrobiology
askedif S GM ;tT$!r..itssmearvye v eterinarym icrobiologisaisn dt hatyous eek thet rainingo pporlunitieasn dt hen umbeor f possibleiobs
provideesn ough viewso nt hist o whichI w ouldc ommenat sf ollows: tendst o beveryli mitedc omparedw itho therdisciplines,
supporfto rv eterinary e,g,p athology,
As someonewhoh asw orkedw ithv eterinary,fooadn d
microbioloHgye,r e plantb acteriologays,w ella sh avingb eeni rainedin m edical TheR oyalCollegoef PathologisStsA Ci nV eterinary
ares omer eaders' microbiologpye, rhapsI a mb etterp ositionetdh anm ostto Pathologhya ss etu pa workingg rouptod eterminethe
responseFsu. rther seet heb enefitsth atc ana ccruefr omn ots tickingri gidly feasibilitoyf v eterinarmy icrobiologisotsb tainintgh eir
corresponoenocne withino uro wni solateda reasT. heren eedsto bem uchm ore membershibpy examinatiosnin cetheo nlyr outea tthe
thisi ssueis w elcome,integratiobne tweenv eterinarayn dm edicaml icrobiologistsmomenits b yp resentatioonf publishewd ork,lshouldb e
emailmtoday@ inp articulabru, ta lsoa crosso therd isciplineass w ell' gratefuliyf ouc ouldk eepm ei nformedo f anydevelopments
sgm.ac.uk Organizationsus cha st heS GM canp laya ni mpodanrto le withint he Societyin t hisa rea,a ndt o offerm ya ssistance'
inf acilitatintgh isp rogression,
t# Clifford Wray,B VM&S MRCVSP hD RFColl'Path.
Thev eterinarytopifcesa turedin t heN ovembeirs sueo f
Mi crobiool gy Toda ywereas ign ifi cantm i l estonea ndd are
I sayp ossiblyo verdueA, rangeo f subjectsw asc overed
althoughth ep otentialzoonoseilse mentappearetod b ek ey
,*.t.ttlqloAnte t imeo r anotherb, eforeI retiredn early1 5
throughout,Thpise rhapsre flectso neo ft hep roblemws ith "E$LsiPyeaagros ,I workedo n influenaz ,C hlamydiap sittaci
veterinarmy icrobiologicraels earcihn t hatthereo ftenh asto
andL is ter ia mo n o c ytoge nesa nd,m orer ecen tly,w as
bea zoonoticli nktoa ttractfundinbgu, tagaine mphasizes
involveidn a minora dministrativwea yi nr esearcohn
thei mportancoef medicalanvde terinarmy icrobiologists
BSE/vCJD,AccordingIl hya, vem uchs ympathywitthh e
workingto gether,Thecrea nb el ittled oubtthatafurther
viewse xpressedb yC olinH owarda ndG eoffreyS childin
similairs suec ouldc overa completeldyi fferenrta ngeo f
their arliclei n Mi crobiologyT oday,
topicsb, othz oonotiac ndn on-zoonotaicn ds tillr emaina s
eng r ossin g ,W ha tw oul d be morep rogr essiveh, owever, Youw illk nowthatCirencestiesrh ometotheR oyal
wouldb ea n issuet hatc oversa rangeo f subjectsb uth as AgriculturalColleagned a lthoughIa mn otawareo f its
bothv eterinarayn dm edicaal uthors(o rfromo ther currenrt esearcohr otheractivitieinst hefieldo f food-borne
specialismwsh erep ossiblefo) re acht opicO' bviousltyh is diseaseo rzoonosesit, m aywelbl ethatsuchin stitutions
wouldr educeth eo veralnl umberotfo picsc overedb,u tI couldb ei nteresteidn t heS GM 'sw ell-conceived
thinki i isw orthc onsiderinagn dt hef ormatc ouldb ec opied oromotioinn t hesea reas.
ford ifferenst oecialismass w ell,
':ER+o yPostle thwa ite, Cir en cester
lam notsurewhattheb reakdowonf v eterinarmy emberso f
theS GMi sb utcouldc onsideratiobne g ivento introducinag
veterinargy roup?S ucha gr oup wasi ntrodu cedb yt heA SM
onl ya fewy earsa go,p riort o whichm ostv eterni ary
Readerws ith responseto the articleo nv eterinarym icrobiology,
membersb elongetdo thec linicagl roup' ,;*:"t!i.:t!u:iii,:t::F.l n
interestisn v eterinary Iw ouldl iket o suggesta fieldf or actionI, believeth at
microbiolosghyo uld Perhapas veterinarysessicoonu ldb ei ncludeda toneo ft he hi gh -resolutiopnh ylogenetsice quenced atabasefso r
notet hef ollowing SGMm eetings;howevienrs ,a yings o lappreciatethatyou microbeosf clinicarle levancewoublde o f enormous
requireto geta na udiencea ndt hism aya gainp ointu sb ack benefittothere searccho mmunitayn ds ocietya like( see
sessionast
towardsz oonosis. http: //rnrww.separationsnowcom/basehtml/S/e 1p,H
forthcominSgG M 13 5 3,6 - 1- 1- O- 74 2- news-detai |- 0- 74 2,OO.html)I, b eI i eve
meetings: I hopet hesec ommentsa reh elPful.
thatthes trongesitm pacto f suchd atabaseso n research
4-iGt e off Fos te r, SA C Vete r i n a ry S er u i ce s, I n v erness wouldb ewitnesseidn v eterinarmy icrobiologl wy,o nder
# TrinitCy ollege ift heS GMw ouldf indw aystol obbyforsucahn
Dublin initiative?
BS eptember2004
+iiL+e vente B od rossy,A u stri a n Resea rch Ce ntres
Zooi'roticin fections
Serbersdort,Austria
rrl Heriot-Watt
University
6Apri2l OO4
Emiergindgi seases
of wildlifea nd
farmeda nimals
1/l\/lY U
FT
t
-
Antimicrobials whele next ?
DavidJ, Payne
The need for new antibiotics is a well known selective inhibition of the bacterial trget. The goal is to Newd rugsa re
concern of health care professionals. Not sur- identify targets that are present in a clinically relevant neededt o meett he
prisingly anxiety over the issue has percolated spectrum ofpathogens with agood selectivity rationale' challengepso sed
'Superbugs:
to the national press with headlines such as bys uperbugs.
Crisis Grows' (Daily Mail,6 December 2003) and WT argetvalidation DavidP ayne
'superbugA pocalypse'( Daily Mail,30 Septembet 2OO3). After selecting an antibacterial. target, the next steps are explainws hy
Remarkabiy, current antibacterial therapy remains proving that it is critical for survival and validating that genomicsa,l though
Iargely dependent on antibiotic classesd iscovered more inhibition of its function will result in bacterial death. A it hasl edt o many
than 20 years ago. Resistance to these antibiotics is vafiety of methodologies have been developed to assess
advancesc,a nnot
increasing (Fig. 1) and, even more worrying, is the this. The simplest is to selectively delete the gene of the
providea llthe
emergence of pan-resistant organisms in our hospitals. targetfrom the genome; if the organism is able to sustain
For many years antibiotic research was focused on growth despite loss of the gene, this demonstrates that answers.
making new derivatives of these established classeso f the target is not essential. Gene regulation approaches
antibiotics, but the pre-existing resistance mechanisms (e.g. inducible promoters and antisense) have also been
are compromising their further development. Conse- used successfully, with essential genes being identified
quentiy, entirely novel classeso fantibiotics are needed by a concomitant decreasei n growth following down
for the future. regulation of the gene. Many of these approaches have
In the mid-1990s bacterial genomics was believed to been optimized to provide rapid throughput target
be the technological advance that would rapidly provide validation. For example, GlaxoSmithKline (GSK) BiLO(Tw0 P):
much needed new classes of antibiotics for the 21st developed robust systems for evaluating the essentiality $$9.$ . Increasreinsgis tatnoce
century. However, here we are in2}O4andno new class of of genes rn H aenoph i lus infl uenzae,S t rept ococucs p ne a mon i a e establischleads soefsa ntibiotics
broad spectrum antibiotic has reached clinical use in the andstaphyloclccus ailreus and more than 350 targets were BELO(BWO TTOM):
last 2O years; the prospects for novel acting antibiotics evaluated. Overall, genomics has enabled the industriali- $$9.* . Industrializoafn toiovne l
being iaunched in the next 5-10 years are frighteningly zationof novel antibiotic target discovery and validation antibiottaicrg edti scovaenryd
low, especially with the alarming withdrawal of many (Fig.2). validation.
companies from this therapeutic area. Consequently,
this review will illustrate how genomics enabled the
industrialization of novel antibioti c target selection and
validation, give an overview of the processesa nd scientific
complexities of progressing from genome to antibiotic
and provide a perspective of where we go from here.
WB acteriagl enomes equencni g
The first bacterial genome was sequenced in 1995 and
with technologies capable of sequencing an entire
genome in just days, it is not surprising that as many as
100 bacterial genomes are now available. \7ith respect to
antibiotic discovery, accesst o a complete genome for a
particular organism reveals all the potential proteins
(targets) that could be exploited as antibacterial
strategies.
WT argetselection
Novel tatget selection is possible on a scale and accuracy
unimaginable in the pre-genomic era' For example, if
seeking a Gram-positive-only antibiotic, bioinformatics
can identify genes only present in clinically important
Gram-positives, but absent from Gram-negatives.
Alternatively, ifdesigning an antibiotic to treat a specific
set of bacterial infections (e.g. respiratory infections or
urinary tract infections) targets can be selected that arc
present in the common causative bacteria. Access to the
human genome also enables evaluation of the potential
selectivity of a novel antibacteri al target. If a human
homologue exists, in-depth comparison with the
bacterial version is necessarv to assesst he likelihood of
&sxswsmxs*s&roYD AYv oLS1/ N /AY@E
F
:
RGIH T: WH ight hroughput
$$9S. .T hceo mplexoifties screening( HTS)
'hits'
chemoicpatli mizoaft ion
Foliowing the identifi-
fromH TtSo a ntibiotdice velopment
candidates, cation of validated, select-
ive targets the next step is
to find an inhibitor of the
target by high throughput
screening of a diverse set
of compounds. Producing
sufficient reagents and
configuring an assay to
be run at high through-
put (screening t 100,000
compounds) can normally
be achieved faiily effici-
ently for antlbactedal
targets, facilitated by the
fact that production of
the many milligrams of
protein needed for HTS can be easily achieved via Once MOA is confirmed, significant medicinal
expression in bacterial hosts. chemical fesources are required to optimize the hit into a
Having obtained high quality hits from HTS, molecule that has all the requisite properties for the
the application of medicinal chemistry is necessary development of a successful antibiotic. This process has
to introduce all the necessary properties for a an additional aspect that is very different from other
'lead
successful antibiotic; this process is known as therapeutic areasi n that ideally the final molecule needs
optimization'. to possessa ntibacterial activity against more than one
pathogen, and optimistically, multiple pathogens.
WH itsfrom HTS Essentially, this means optimizing the inhibitory
Identification of hits and the lead optimization steps activity against the target from each ofa key spectrum of
(Fig. 3) are the two most challenging aspects of deliver- pathogens. Although the target is deliberately selected
ing new antibiotics from genomics. First, the hit rate of to be highly conserved across these pathogens, the
HTS of antibacterial targets is less than that achieved for architecture of the active sites will differ slightly, which
targets from other therapeutic areas.G SK basest his by can add to the challenge offinding one molecule that fits
comparing data from gther therapeutic areasw ith the all. Furthermore, even if a molecule has been identified
results of more than 10 screens run on antibacterial that has equal inhibitory potency against the targets
targets. There may be a combination of reasons, but from all the key organisms, considerable challenges still
analysis of the chemical properties and parameters exist in optimizing penetration through the bacterial
of known antibacterial compounds suggests that such wall and membranes which arc characteristically diff-
properties may not be well represented in standard erent in each species. Consequently, it can take a con-
'anti-
screening collections and a broader or more siderable effort to identify molecules that demonstrate
bacterially relevant'diversity has to be acquired and good target inhibitory activity and thus antibacterial
screened. Consequently, the poorer hit rate from HTS of activity acrossm ultiple pathogens.
antibacterial targets compromises successa t the earliest Then, whilst maintaining the broad antibacterial and
step in the cascade. tar get i nhi bi tory activ ity, other important att ributes are
necessary.T hese include favourable pharmacokinetics
ffiL eado ptimizationo f hitst o antibiotics (PK), efficacy in animal models, lack of toxicity and even
It is likely that a hit from HTS will possesss elective parameters such as appropriate solubility, stability and a
micromolar inhibitory potency against the target with commercially viable synthetic process (Fig. 3). One other
Iow-level antibacterial activity. At this early stage it is challengin g factor is that we are often dealing with
imperative to demonstrate that the compound's anti- an entirely new chemical entity that has never been
bacterial effect is clearly a result of inhibition of the previously evaluated for pharmacological activity and so
target and not due to potentially non-specific effects. no structure activity reiationship (SAR) exists. This is in
Providing robust mechanism of action (MOA) data can contrast to delivering new derivatives of established
be highly complex and requires significant biochemical classeso f antibiotics such as cephalosporins, macrolides
and complex proteomic and gene expression approaches or quinolones where decades of SAR exist to facrlitate
(e.g. gridding). the lead optimization process. Finally, once a molecule
E ffi $*ffiffifff#if i tu#ffi\eroDrvvol3'l /MAY04
'ii
I
it'
has been identified with all the requisite preclinical provide the substantial medicinal chemical resource Further reading
properties, it enters the development phase. Here, good, necessaryt o develop promising antibiotic leads that act
Gentry, D.R., Ingraham,
predictable animal infection models and relatively rapid on these rargets. As part of this straregy, a feturn ro
K.A.,Stanhope,MJ.,
clinical trials with cleady defined end points facilitare a microbiology is required to provide high quality and
Rittenhouse, S.,J arvest,
higher probability of successt han in some other thera- fast in uiuo and in aitro microbiological evaluation R.L., O'Hanlon, PJ.,
peutic afeas. of promising preclinical antibacterial compounds. Brown,J.R. & Holmes, DJ.
Success at high throughput screening also needs to (2003).V ariables ensitivityt o
WB utt herea res urprises...
be addressed. Acquisition and generation of novel bacterial methionyl-tRNA
Progressing a project to identify an antibiotic with an compound libraries especially suited to the chemical synthetasein hibitors reveals
entirely novel mechanism of action can be an adventure pafameters common to antibacterial compounds - subpopulatio ns of St rept ococcus
into the unknown compared with finding new deriva- 'antibacterial targeted chemical diversity' - is one pneun oni aew ith two distinct
tives of established classes of antibiotics. This is welcome approach. In addition, screening new methionyl-tRNA synthetase
genesA. nt imi crob A gents
exemplified by the methionyl rRNA synrherase (MRS) generations ofnatural product diversity, such as gene
Cb enothe4r 7, l7 84-17 89.
tatget. This target is essential in a broad spectrum of shuffling of known secondary metabolite pathways,
bacterial pathogens, and as part of a strategic effort to could also yield new compounds to screen against Jorgensen, J.H. & others
screen all 19 of the Gram-positive IRNA synthetases antibacterial targets. (1990).A ntimicrobial
Resistancea mong respiratory
we identified a promising inhibitor of MRS. Chemical In conclusion, since 1995 big pharma and the
isolateso f H aeno pb i I us
optimization of this hit successfully yielded highly biotech industry have applied immense resources ro
influenzae,M oraxella
potent antibacterial compounds which cured multi- exploiting genomics in an arrempt to identify new cat arr baI i s, and St rept ococc us
resistant bacterial infections in animal models. However, antibiotic molecules. Although this has provided pneurnoniaien the United
it was found that the MRS (MRSI) screened in the an unprecedented number of antibacterial strategies, States.A n t irni crob A gents
HTS only existed in around 50 % of ciinical isolates success measured in terms of new antibiotics has Ch ernohte r3 4. 207 5 -2080.
of Str. pneumoniae;t he other 5O 7o possesseda different been disappointingly poor. This, along with changing KarlowskyJ.A. &others
MRS, MRS2. Despite overall high similarity between corporate priorities and regulatory issues, has contri- (2003).F actorsa ssociated
MRS1 and MRS2, this chemical seriesa chieved potenr buted significantly to many companies withdrawing with relative rateso f
inhibition of MRS1, but inhibition of MRS2 was from antibiotic research, despite the fact that the antimicrobial resistance
severely compromised becauseo fa leucine to tryptophan medical need for novel acting antibiotics remains among St reptococcpu nse umoina e
difference in the acrive site of MRS2. Consequently, unquestionable. At GSK we hope to increase prospecrs in the United States:r esults
the series possessed unacceptably poor antibacterial for delivering new antibiotics by applying significant from the TRUST Surveillance
activity against 1O % of alI Str. pneumoniae clinical microbiolo gical and medicinal chemistry resources ro Program ( 1p 98-2002). C / in
isolates. Extensive efforts to modify the molecule to tackle directly the preclinical challenges and use rhe lnfut Dis 36,963-970.
achieve inhibition of both MRS rypes whilst very considerable knowledge from bacterial genomics
maintaining its other drug-like qualities failed. This to facilitate the successo four antib acteialresearch.
experience illustrates the need for target validatioq
beyond the genome, emphasizing that the genomes O Dr David J Paynei s Director of Microbiology
we have accesst o only represent the genetic make up in the Mi crobiaLM uscubskebtal and Proliferative
of a single organism which may not be entirely DiseasesC E D D at G laxoSm i thK li n e . So u th
represenrarive of its species. CollegevilleR d,C ollegevilleP, Al9426, USA.
em a iI da vid _ j _payn e @gs k .c om
WWheren ext?
It is easyt o accuseg enomics of not delivering! However,
this is really not true as genomics could only ever
identify novel antibacterial targets and new genomic
technologies. Due to genomics, we now probably know
all the potential ways ro kill bacteria and experiments
previously conducted on a gene scale can now be
performed to give readouts on rhe enrire genome.
Making antibiotics from genomics depends heavily on
high throughput screening and successful optimization
of hits from these screens. The preclinical complexities
and hurdles of these factors were underestimated in
the genomic era and are rhe two main issues that have
compromised the delivery of antibiotic development
candidates and thus new drugs.
So where do we go from here? Antibiotic researchn ow
needs to focus on thoroughly validated targets and
&s$ffiffiffiffi$sessroYD rv vol3 1/ MAY04r
,
Antiviral drugs ashort historyof
their discoverya nd development
HughJ .F ielda ndE rikD eC lercq
Form anyy ears ,':Tll'h e concept of specific antiviraltherapy
Selected milestones in anliviral drug
itw asb elieved and a false dawn development
thatt herew eren o The 1946e ditiono f van Rooyena nd RhodesV' irus
effectivaen tiviral Diseaseso f Man introduced the concept ofspecific therapy 1951B -ThiosemicarbazonHea nereta l,
drugsS, inceth e for a number of virus infections, including mumps and 1957l nterferon lsaacs&Lindenmann
late1 9 50s smallpox. This early work focused on the use of the 1959| D U Prusoff
current bacterial antibiotics, including sulphonamides.
scientishtsa ve 1961H ydroxybenzylbenzTiammitd,mE ag zogleer s
The futility of these early attempts led to the dogma that
madeg reat 'antibiotics'
viruses are not susceptible to and for two 1961G uanidine Barrer&aM- Oerlon ick
progresinst his
decadesv irologists were taught that selective toxicity for 1962I D(Uc linicaleffectiveKnaeusfsm) an
arcaasH uqhF ield
these obligate intracellular parasites was unattainable.
andE rikD dClercq Several lines of researchw ere to overturn this iddefixe. ,1nnd963M arboran(clinicalefBfeacueteitvrae ln, ess)
describe, In 1957 came the famous first description by Isaacsa nd 1964i FT(c liniecfafel clivenessK) aufman
Lindenmann of interferon. Human interferons wefe 1964A mantadine DaviHeos,f fmeatnanl,
subsequently developed for the treatment of particular 1964A ra-A PrivdaeGt ari&lhD eeR udder
virus infections, i.e. hepatitis B and, more recently,
1972R ibavirin SidwReoll,b eintas l
hepatitis C virus infections, as pegylated interferon,
19i6 Ara(-cAl iniecfafel ctivenesWsh) itley
combined with ribavirin. However, the discovery of the
interferons in the late 1950s was something of a false 19il Acyclovir Elion,Schaeffer,Collins&Bauer
dawn. 1978D HPA DeC leracH qo ly
,ril doxuridine:t hefirst useful antiviral 1979P hosphonaocfio(dPr mFAic) Helg$raa0 nbde rg
nucleosidea nalogue 1979B VDU DeC leraclqa l
Many in the antiviral field recognizeasamost important 1982G anciclovir Verhe&yJd ,eCMn, artin
early milestone the description of )-iodo-2'-deoxyuridine 1985A zidothy(mAiZdTin)e MitsuByrao,d eetra l.
(idoxuridine, IDU) by Dr Bill Prusoff in 1959 and '1986
dddl d0,, ,, MitsuByaro&d er
the realization of its antiviral properties. The first
1986A defovir(PMEA) DeC lerHcqo,lr y;t al,
publications on this and similar nucleoside analogues
appeared in cancer journals and it is clear that the 19870 idof(oHvPirM PC) DeC lerHcqo,el yt al.
aim was to develop molecules to interfere with DNA 19BgF amcic(loorvapirlr odr$urga tegHy)a rndVeenrH,e o degtea l
synthesis in order to produce cytostatic or cytotoxic
19BgH EPT/TIBO DeCleBracqb a,Pauwelss,
drugs for the treatment of neoplastic disease.H owever, 1990 Janssen
an important by-product of this work was the discovery
1990S aquinavir J,AM, artRino,b eer/tasl
that IDU was a specific inhibitor of certain large
DNA viruses, most notably herpes simplex virus (HSV). 1991s TC Belleeatua l,
The compound is cytotoxic and was therefore only 1993T enofovir(PMPA) BalzaDrieCn il,e rncH qo ly
suitable for topical application, for which it remains 1993R elenza volntz steetina l
in use to the present day. The development of IDU from
19970 seltamivir Kint,tal,
laboratory inhibitor to useful antiviral drug was driven
by several notable pioneers, especially the ophthal-
mologist Dr Herbert Kaufman who proved its clinical ,ii$Pro li omyeli tis,s ma I I p ox:i m p ortan t ear ly
value in 1962 and, subsequently, that of trifluoro- antiviratla rgets
thymidine (TFT) in f964. S7e will return to herpes antivirals, but first we should
The first description ofthe antiviral activity ofadenine remember the origins of several other lines of antiviral
arabinoside (vidarabine , ara-A) by M. Privat de Garilhe researcha nd the early pioneers. Poliomyelitis was still a
and J. De Rudder also dates from the avant-garde year serious threat in the developed world when guanidine
1964. Ara-A was the first of the nucleoside analogues to and 2 - (u -hyd roxy b en zy l)b en zi mi dazole ( H B B ) we re
be sufficiently non-toxic to be given systemically and the shown to be specific inhibitors of this small, positive-
work of Dr Richard \Thitley proved beyond doubt strand picornavirus and other picornaviruses (i.e.
the clinical value of this compound, showing for the Coxsackiea nd Echo) ase arly as 196I byJ.G. Barrera-Oro
first time that, providing treatment was commenced and Joe Melnick, and Igor Tamm and Hans Eggers,
early in the disease,it wasp ossiblet o curtail herpesz oster respectively. The latter promoted the concept of specific
in the immunosuppressed and reverse the potentially antiviral therapy for polio and their lectures and writing
lethal progression of herpes encephalitis and the much influenced the field in the 1960s, although, in the
overwhelming herpes infections that occasionally occur event, polio was eventually controlled by vaccination
in the newborn. rather than chemotherapy. Another important virus
E ,,.,;;;i- l,:i'rT OIIAYVOL3 1/ MAY04
threat was that of smallpox
caused by variola virus,
which is among the largest
of all virusesw ith a double-
stranded DNA genome
comprising more than
200 genes. The compound
B-thiosemicarbazone was
first reported to be an
inhibitor of a related
poxvirus, vaccinia virus,
in 19tI by D. Hamre.
K.A. Brownlee and R. Donovick. DrJohn Bauer ar rhe of 4-guanidino-Neu5 Ac2en (relenza), the first NA ABOVE:
then S7ellcome Foundation Laboratories in Beckenham, inhibitor, to be marketed by Glaxo. A difficulty with this Pictutarek eantt h ei0 th
UK, led the team which developed the drug marboran, a compound is its poor oral bioavailability, necessitating InternatioCnoanl fereonncAe n tiviral
ResearActhla nt6a- 11A pri1l 992
B-thiosemi carbazoned erivative. Marboran was shown its application by means of inhalation. Other NA Manoyft hosien t hisp hotograph
in several trials to have some clinical efficacy both for the inhibitors tailored on rhe sialic acid residue followed, havme adaem ajocro ntributtioon
treatment of smallpox and the complications of vaccinia including the successful oseltamivir (developed at thed evelopomfa enntitv irals
following vaccination. Furthermore, it was shown that Gilead sciences and first reported by C.U. Kim et al. in 1,G L GalassMor;Gs2 ,a lasso;
3 W.HP rusofEfR; 4K ern;
marboran was a highly effective agenr for chemo- 1997) in which a cyclohexene ring was introduced and a 5,R FS chin6a JzC i;M artin;
prophylaxis in the management of smallpox contacrs. polar glycerol replaced with a more lipophilic side-chain. 7G B E lionR;8.JW, hitley;
Smallpox was shortly to be eradicated by means of the Furthermore, oseltamivir is an erhyl esrer thar is orally 9,HJF ieldI;-1L0l mbach;
\)fHO vaccination scheme and work on marboran bioavailable and readily converted to rhe active carboxy- 11[ /rsShigeStaS ;]h2i geta;
ceased. However, recently there has been renewed late by esterasesin the liver, aprodrug approach first used 13,DLCio ttaJ;A1S4 ecristlll;
15J,. -CG rac1ie6tL ;J .S tuyver;
interest in antipoxvirus agents as a result ofthe threat of for the antiherpetic compound famciclovir (seeb elow). 1ZDP arker;1CBu,CsiRc k;
smallpox being reintroduced by an act ofterrorism. 19K S hock2le0By 0 ; bers;
:,$T,h ef ir st broad- spectrum an tivir aI after 21K Y.HostetAle Krw;2o2n g;
$ Treatmentsfo r in fI u enzav ir usi n fections interferon 23,C[/ lcGuigaRnW;S2 i4d well;
25K .KB iron;J2W 6[ ,/ ellors;
Influenza was also an early antiviral target, and in 1964 Ribavirin was reported in 1972 by Robert Sidwell, 27E D eC lerc2q8P; D G riffiths;
it was reported by C.E. Hoffmann and co-workers that R.K. Robins and their colleagues as a broad-specrrum 29L,[ /.M ofensoJn,P; 30,
amantadine was a specific inhibitor of the negarive antiviral acting against many different virus families, SommadoAss [/io;3ll1a ;
RNA strand virus, influenza A. Amantadine and its notably the negative RNA strand virus, respiratory 32D, S chae3ff3eC rL.; aughlin;
sister compound, rimantadine, were later shown to act syncytial virus. It was noted that virus resistance to 34N B ischofberger
COURIDERSR YA YfuFlOS NCDH INAZI
by interaction with the viral M2 protein which forms an . ribavirin was not detected for any of the susceptible E[/ORUYN IVERGSAIUT SYA
ion channel during the early stageso f virus replication. virus families. This may be related ro the fact that
As for almost all other specific anriviral agenrs, resistanr ribavirin primarily rargers a host-cell protein, and,
mutants were obtained by passage of virus at sub- indeed ribavirin (5'-monophosphate) has been found to
inhibitory concentrarionso f the inhibitor and in this case inhibit IMP dehydrogenase, the enzyme responsible for
these mutations mapped to the M2 and haemagglutinin the conversion of IMP to XMP. Another discovery in
(HA) genes. Furthermore, when the compounds were the 1970s was the antiherpesvirus activity of the pyro-
used clinically, resistanced eveloped quickly in patients phosphate analogue phosphonoformic acid (phosphono-
and this was one of the factors which argued against their formate PFA) following the earlier discovery of the lead
widespread clinical use. Rimantadine was, however, compound, phosphonoaceric acid (PAA). PFA, described
widely used clinically in Easrern Europe during the by B. Oberg and developed at the Swedish pharma-
cold-war years, although the data relaring to its use in ceutical company, Asrra, suffers from toxicity problems,
man were not so easily forthcoming. However, the work including nephrotoxicity. However, PFA conrinues to
on amantadine and rimantadine provided a platform for have a role in managing HSV infections in immuno-
the development of the next generation of anti-influenza compromised patients who are resistant to the classical
drugs that resulted from a programme of rational drug antiherpetic compounds (e.g. acyclovir).
design. The crystal strucrures of the influenza envelope
proteins - HA and neuraminidase (NA; - were solved. ,l,iit'Thaed vent of acyclovir
Influenza NA was known to interacr with sialic acid No history of the origins ofantivirals would be complete
residues on host-cell plasma membranes and the first of without acknowledging the enormous impact of the
severals ialic acid analogues, NeuSAc2en, designed by compound acyclovir. Like IDU, acyclovir was rhe result
M. von Itzstein and his colleaguesj n 1993, basedo n the of a drug developmenr programme nor primarily aimed
crystal structlrre of influenza NA, led ro rhe development at antivkals. The names of Dr Gertrude (Trudy) Elion
*\S$SNrS$frfi, *$*$*\dIO' DAY VOL g 1/ MAy04 E
Deoxyguanosine Acyclovr(ra ciclovir) Vargancicrovir Ritonavir
*N_Jl.-_-\
o lti )
{x} HrC.
-| tl HrnAN^[ o ,CH. I
ux/\-Nrl ) esterase I I Hi
u' s^/-'\N'-\ry\,-n!
tlrttoi^x_'ll- N I H'N,^-N/--f f{"" \ {x's { /O *t O |I ,1rt -tNI Ci H,r H Oii Il
_0_ | { r{ </-\ grc'-"{ .-"\
i\.-/I-l no- , ',.tt'- t$"l{l {r$$} ) cHr ivi i
OH
OH
ABOVE: and Dr Howard Schaeffer (Burroughs \flellcome, USA) Pharmaceuticals company. Against HSV penciclovir is
Ihec hemicsatrlu ctuorfea are inextricably linked to this compound, although its comparable in activity and specificity with acyclovir.
selectoiofa nn tivicraolm Poundspotent antiviral properties were first uncovered by Drs The realization that penciclovir has even poorer oral
oRfa enidst ui vsireactldo om i npdoiucnatwdthesho i cshPde ia ffretrs Peter Collins andJohn Bauer at the \Tellcome Labota- bioavailability than acyclovir resulted in aprogramme of
fromth en atursatlr uctufrroem tories (UK) where the compound had been sent for medicinal chemistry led by Dr Mike Harnden which
whicthh eayr ed eriveBdlu.i es antiviral activity evaluation. Dr Bauer coined the term culminated in the synthesis of the molecule that was to
usetdo d epitcht ec omPoneonfts acycloguanosine, although this was subsequently become famciclovir. The key point here is this was the
prodrutghsaa t rere movbeYd dropped in favour ofthe generic term acyclovir (aciclo- first antiviral orally avaiiable 'prodrug' (to be later
eanctziyvcmeoa imcct pioolnnur nlrdostYo. ield vir). Dr Elion and her colleagues produced a definitive marketed) and brought about a strategy that has been
Am orceo mplesteeot fs tructuresmechanism of action and the thoroughness of this work widely repeated for many other antiviral compounds.
accompatnhieeo sn linvee rsioofn and the associated pharmacolo gical data were crucial to Famciclovir is rapidly absorbed when given orally and
thisa rticaletw ww.sgm,ac.ukthe early acceptance of the compound. Acyclovir was then converted to the active antiviral compound,
shown to be a substrate for the HSV-encoded deoxy- penciclovir in aiuo, following host enzymic conversion
ribopyrimidine kinase, usually called thymidine kinase by two esterases teps and an oxidation step' In parallel
(TK). Acyclovir monophosphate is then further phos- work, Burroughs \Wellcome developed several potential
phorylated by cellular kinases and the resulting acyclovir prodrugs ofacyclovir and one ofthese was the valine ester
'valaciclovir'
triphosphate is a potent suicide inhibitor of the herpes- of acyclovir which came to be known as
specified DNA polymerase. The fact that a (deoxy)- which is currently in widespread clinical use (for the
guanosine analogue serves as a substrate for the virus same clinical indications as acyclovir). In fact, the first
deoxyribopyrimidine kinase was a major stumbling prodrugs to be described (back in 1981 by Hubert
block in elucidating the mechanism of action, but Vanderhaeghe and his colleagues at the Rega Institute)
eventually this was resolved. Acyclovir has become were the amino acid (glycine, alanine) esters of acyclovir,
recognized as one of the safest drugs of all times with designed to make acyclovir more soluble in water' The
almost no adversea ffects described during 2r lz decadeso f prodrug strategy has now been widely adopted and the
use (apart from those related to low aqueous solubility neuraminidase inhibitor produced by Gilead, oselta-
of the compound), including individuals who have used mivir, is one recent example (see above);valganciclovir,
the compound for 2O yearc to suppress recurrent HSV' the valine ester ofganciclovir being another one.
Acyclovir was the very first highly selective antiviral
compound, and it was the prototype described as a $SH IV - a newvirus threat
'second generation' nucleoside analogue. It eventually The scienceo f antiviral researchw asw ell advancedw hen
became available as an over-the-counter drug in the UK' HIV/AIDS appeareda s a major new virus diseasein
an unthinkable development even a few yearsp reviously. the early 1980s.T he first effectivea ntiviral compound
(LZT,azidothymidine) wasa lreadya mong the library
$ST he prodrug strategy for en hancing oral of compoundss creenedb y Burroughs \Tellcome and
bioavailability the National CancerI nstirute (USA), and wasp romptly
The fact hasr emainedt hat its low oral bioavailability reportedi n 1985 to bea specifici nhibitor of retroviruses,
givesa cyclovira pharmacologicadl isadvantageS. everal including HIV. The mechanismo faction of AZT isbased
BELOW: new analoguesh ad been discoveredt o have similar upon phosphorylationo f the drug by cellulare nzymesto
Ap agoeu ot fN ic0kl ivesr antiviral properties in particular bromovinyldeoxy- AZT tdphosphatew, hich then interactsa t the substrate-
sntortuecbtuoasrohnekdof i wrsitdtnh egecs hcreimptiinicoanl uridine (BVDU), synthesizedb y Phil Barr in the binding site of the HIV reverset ranscriptaset,h ereby
197o4ft hea ntiviaraclt iviotYf Laboratoryo f StanJonesa nd Dick \Talker at the Chem- acting as a chain terminator. The discoveryo f AZT
acycloguanTohsecino en.c lusisionis try Departmenta t the University of Birmingham (UK) was followed by several other dideoxynucleoside
'very
activien;v estigfuarteth er' and shown to be a potent inhibitor of HSV (type 1) (ddN) analogue(sd dl, ddc, d4T,)TC, ABC, (-)FTC) so
IMARGEEP RODWUITCKHEIN DD and the related varicella-zosterv irus (VZY) by Erik that at the time of writing sevend dN analoguesa, lso
PERMISOSFGI OLANX OS[/IIiHKLINE,
NICOKL IVAENRPD E TCEORL LINSDe Clercq at the Rega Institute of Medical Research referredt o asN RTIs (i.e.n ucleosider eversetr anscriptase
(Belgium). BVDU is now on the market in Germany inhibitors) are formally licensed for the treatment
il {f' ..1,r.it,1 -.i.dl ;. ; ,r .l ando ther Europeanc ountriesf or the treatmento f herpes of HIV infections.A II theseN RTIs act in a similar
zoster( shingles).A cyclic guanosinea nalogueso ther fashion:a fter their phosphorylationt o the triphosphate,
,t
# ,.\ than acyclovirw eres ynthesizedin severalla boratories they interacta s'chaint erminators'oft he HIV reverse
il \, \ i\}*,o:"", -)xii''--. ""I;I r'', Jwthuoalrital dlnwa Vtiederer o,h onen ywedo oefu nthla don sfdieJn b odeh iann g nC gi.ca Mhneac iircntli ontvh tiehr( edtrnies acatot mSveyernnettdeb o xyf) ptinrrafoenvcsitrciaorliu pDstas NstAaet ,te ht( uhfosal tlp oorwethivneegrn witniintsegeg wtrhaoetu iofldon r omefta ethtrineoa npl riozofev ttirhhaeel
irIl! cytomegalovirus (CMV) infections in immuno- DNA into the host-cellg enome).
suppressepda tients. ln I99O it camea s a surpriset hat the HIV reverse
{*.i-- ,, Another acyclicg uanosinea nalogue,p enciclovir,w as transcriptaser evealeda secondt a:^gefto r interaction of
i..i-r& .".-.r.1^.{r. l_{.rL developedi n the laboratorieso f the former Beecham HIV RT inhibitors. namelva t an allosterics ite, distinct
E R$$ffiffiS$fffif [i -#ffiWroDAYVOLS1 / MAY04
f
fl
Relenza Amantadine Marboran
*o\
I H
?',
o Ho-"'voH i
iJii '--fli "!-o o i tt-\ -l- - N\.
N',- - nrc\.,N{H /\// ii l i:o
H $-_*r ll f' i*4, oH .,,N H".HCI V^*{ i:il s !
o HN' N- -C-
\ N NHz
NH H
')t::tt::
HzN
from where the NRTIs interact. This site was originally phosphonatesT.h esen ucleotidea naloguesc anb ev iewed Further rcading
dubbed the TlBO-binding site, as TIBO, together with asa kind of hybrid betweena cyclicn ucleosidea nalogues
DeClercq,E. &others
HEPT analogues, were the first compounds found (by (a classo f moleculest o which acyclovit,g anciclovir and
(1986).A novels elective
E. De Clercq and his colleagues) to interact in this way. penciclovir belong) and pyrophosphate analogues broad-spectruma nti-DNA
Latet, a succession of structurally different compounds, (phosphonoacetiacc id and phosphonoformica cid),t hus virus agent.N ature3 23,
now termed NNRTIs (non-nucleoside reverse trans- combining the assetso f both approachesI.n this sense 464467.
criptase inhibitors) were shown to interact in a manner HPMPA could be considereda hybrid of PAA (phos-
Elion, G.B. & others (1977).
similar to that ofTIBO and HEPT, and ofthese NNRTIs, phonoacetica cid) wi th DH PA (2,3- dihy droxypropyl-
Selecriviryo faction ofan anti-
three, namely nevi rapi ne, delavirdi ne and efaviren z, hav e adenine),a moleculed iscoveredin I978 by De Clercq herpetic agent , ) -(2-hy droxy-
been currently licensed for clinical use in the treatment and Holy asa broad-spectruma ntiviral ageflt,but at that ethoxymethyl)gu ani ne.
'nucleotide'
of HIV infections. time overshadowebdy acyclovir.A s the first ProcN atl Acad SciU SA 74 -
The elucidation of the HIV genome revealed at an analogue,t o be endowed with antiviral properties, t7 16-5120.
eady stage the existence of the virus-specified protease HPMPA would subsequentlyg ive rise to numerous Pauwels, R. & others
and this was the declared tatgetfor several of the leading derivatives,t hreeo fwhich would eventuallyg ain formal (1990).P otenta nd selective
pharmaceutical companies. The team of chemists and acceptancefo r the treatment of a wide variety of virus inhibitionofHlv-1
molecular virologists at Roche led by DrsJoe Martin and infections: cidofovir for the treatment of herpes- rcplication i n ui tr o by a nove l
Noel Roberts achieved the synthesis of saquinavir, the virus infections( CMV in AIDS patients),a defovirf or serieso fTIBO derivatives.
first peptide-based transition state mimetic. Saquinavir the treatmento f chronich epatitisB and tenofovirf or the Nature343,4l0474.
was shown to be active at nanomolar concentrations treatment of HIV (AIDS), the latter two in the form of Prusoff, \W.H.(I95r.
and was among the most potent antiviral substances yet their oral prodrugs, adefovird ipivoxil and tenofovir Synthesisa nd biological
described. Saquinavir was soon joined by several other disoproxil, respectivelyC. idofovir, in addition to the activitieso f iododeoxyuridine,
similar compounds produced by competing companies. indication for which it hasb eenl icensed( CMV retinitis an analogo f thymidine.
At present, seven protease inhibitors have been licensed in AIDS patients), also offersg reat potential for the B iochix t B iopbys A cta 32,
for the treatment of HIV infections: saquinavir, rito- treatment of papilloma-, adeno-,h erpes-( other than 295-296.
navir, indinavir, nelfinavir, amprenavir, lopinavir and CMV) and poxvirus infections (i.e. vaccinia,v ariola, Sidwell.R.W. &others
atazanavft. monkeypox, molluscum contagiosum, or0. This is (I97 2). Broad-spectrum
2003 witnessed the advent of the first'HIV fusion' gratifying knowledge,a sc idofovir may be useful in the antiviral activity of virazole:
inhibitor, enfuvirtide (previously called 'T20'), which prophylaxisa nd/or therapyo f variola virus infections 1- B-o-ribofu nnosyl- I,2,4-
blocks viral entry by tatgeting the viral glycoprotein (smallpox)a nd complications( sucha sd isseminatedo r triazole - 3 - carboxamide.
SciencelT,T70 5-706.
gp41 which is responsible for the fusion of the viral and progressivev accinia)f ollowing vaccinationw ith the
cellular membranes. A problem with this compound is smallpox vaccine vaccinia in immunocompromised Whitley,RJ. &others
that, unlike all other anti-HIV drugs, which can be parienrs. ( 1976).A deninea rabinoside
therapy ofherpesz osteri n the
administered orally, enfuvirtide has to be given sub-
immunosuppressed.N IAID
cutaneously by injection twice daily. S Conclusions
Collaborative Antiviral Study.
It should be mentioned that virus drug resistance hls Many decades after the birth of antibiotics, antivirals
N EnglJ Med2 94, ll93-1T99.
not been a problem with herpesvirus chemotherapy have, at last, definitely come of age * 37 antiviral drugs
(except in immunocompromised patients). However, have been formally approved for the treatment of viral
resistance to antiviral drugs has emerged as one of the diseases. Their applications are primarily aimed at
most imporcantbarriers to efficacy in the treatment of therapy of herpesvirus (HSY VZV CMV) as well as HIV,
chronic infections, including HIV. In this caset he key HBV. HCV and influenzavirus infections. Concomitant-
was to be found in history - the treatment of tuberculosis ly with the availability of so many antiviral compounds,
where cocktails of drugs were found to be necessary the genome sequences of many viruses have become
for the successful eradication of the mycobacteria over available, and the structure and functions of many virus
several months. There has been considerable opposition proteins known, thus defining novel specific targets
to the possibilities of drug combinations in the antiviral for rational drug design. The difficulty of translating
field (probably born from their inherent reputation for specific inhibitors into effective drugs remains a major
toxicity); therefore, the introduction and subsequent task for the medicinal chemist and'serendipity', which
recognition of the value of drug combinations for the has aided virologists on several notable occasions in the
treatment of HIV infections were not instantaneous. but past, will likely still have a role to play in the future.
are now taken for granted.
a H. J. Field, Centre for VeterinaryS cience,
WT hea cyclicn ucleosidep hosphonates Universityo f Cambridge,M adingley Road,
The discoveryi n 1986 of HPMPA or (S)-9-(3-hydroxy- Cambridge,C BS OES,U K and E. De Clercq,
2-phosphonylmethoxypropyl)adenineb, y Antonin Rega lnstitute for Medical ResearchK, atholieke
Holy and Erik De Clercq, heralded atotally new concept UniversiteiLt euven,B -300OL euven,B elgium.
in the antiviral therapye ra,t hat of the acyclicn ucleoside
w$ffiffisffi$sessYro DAY vol3 1/ MAY04E