Download - 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
© 20 Macmillan Publishers Limited. All rights reserved10