Adenosine Analogue Blocks Dengue Infection

Dengue virus (DENV) is a favivirustransmitted by msquites that

affects up t 100 miin pepe eachyear. Infectin can be ife-threatening,and there are currenty n avaiabe

 vaccines r antivira therapies.Writing in PNAS, Yin and ceaguesdescribe a nve adensine anague

that is capabe f ptenty inhibitingDENV infectin.

DENV is mainy fund in the

trpics, and infectin is character-ized by headache, musce and intpains, fever and rash. The marity 

f deaths are due t the devep-ment f dengue haemrrhagic fever

(DHF) and dengue shck syndrme(DSS). The existence f fur DENVsertypes has severey chaenged the

devepment f effective treatments.Given that nuceside anagues haveprven effective in cmbating ther

 viruses, Yin and ceagues set ut tdetermine whether such an apprachcud simiary be appied t DENV.

First, the authrs anaysed mrethan 90 previusy undescribedadensine anagues. NITD008

(which differs frm adensine by acarbn substitutin fr N-7 f thepurine ring and an acetyene grup at

the 2’ psitin f ribse) was fundt be a ptent in vitro inhibitr f the DENV RNA-dependent RNA

pymerase (RdRp), inhibiting afur DENV sertypes and signifi-canty reducing vira titres in varius

ce ines. The effects f NITD008were specific t Flaviviridae famiy  viruses: it simiary inhibited West

Nie virus (WNV), yew fever virusand Pwassan virus.

Using a primer extensin-based

RdRp assay, the authrs shwed thatNITD008 inhibited DENV RdRp by causing terminatin f RNA chain

synthesis. Imprtanty, cntinuuscuturing f DENV r WNV

in ce ines with NITD008 fr upt 4 mnths did nt ead t theemergence f resistant strains.

T assess the therapeutic pten-tia f NITD008, mice were infectedwith DENV-2 and immediatey 

administered NITD008 ray twicedaiy fr 3 days. Peak viraemia and

pasma eves f vira nn-structuraprtein 1 (NS1) were suppressed upt 35-fd and 14-fd, respectivey.

A deayed start f treatment up t48 hurs pst-infectin as reducedpasma viraemia by 7–10-fd.

Furthermre, simiar treatmentf a etha dengue muse mde,in which mice devep hamark 

characteristics f DHF and DSS,cmpetey prtected mice frmdeath. Mice were as prtected

when treatment was deayed by up t 24 hurs.

Imprtanty, n bserved adverse-

effect eve cud be achieved whenrats were dsed ray with NITD008fr 1 week. Hwever, txicity was

bserved in rats and dgs treated fr2 weeks. Experiments are in prgresst investigate the cause f txicity 

and vercme the side effects,athugh the authrs emphasizedthat treatment duratin wud be

expected t be ess than 6 days frthis acute disease.

Tgether, these data supprt the

future devepment f a nucesideinhibitr fr the treatment f DENVinfectin. Such an apprach might

as be brady effective fr the treat-ment f ther favivirus infectins.

Sarah Crunkhorn

ORIGINAL RESEARCH PAPER Yin, Z. et al.

An adenosine nucleoside inhibitor of dengue

virus. Proc. Natl Acad. Sci. USA 16 Nov 2009

(doi: 10.1073/pnas.0907010106)

A N T I V I R A L D R U G S

Adenosine analogue blocks dengue infection

R e s e a R c h h i g h l i g h t s

NATURE REVIEWS | Drug Discovery  VolUME 9 | jANUARY 2010

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