ANTIVIRAL DRUGS Adenosine Analogue Blocks Dengue Infection

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ANTIVIRAL DRUGS Adenosine analogue blocks dengue infection

Dengue virus (DENV) is a flavivirus of deaths are due to the develop- administered NITD008 orally twice transmitted by mosquitoes that ment of dengue haemorrhagic fever daily for 3 days. Peak viraemia and affects up to 100 million people each (DHF) and dengue shock syndrome plasma levels of viral non-structural year. Infection can be life-threatening, (DSS). The existence of four DENV protein 1 (NS1) were suppressed up and there are currently no available serotypes has severely challenged the to 35-fold and 14-fold, respectively. vaccines or antiviral therapies. development of effective treatments. A delayed start of treatment up to Writing in PNAS, Yin and colleagues Given that nucleoside analogues have 48 hours post-infection also reduced describe a novel adenosine analogue proven effective in combating other plasma viraemia by 7–10-fold. that is capable of potently inhibiting viruses, Yin and colleagues set out to Furthermore, similar treatment DENV infection. determine whether such an approach of a lethal dengue mouse model, DENV is mainly found in the could similarly be applied to DENV. in which mice develop hallmark tropics, and infection is character- First, the authors analysed more characteristics of DHF and DSS, ized by headache, muscle and joint than 90 previously undescribed completely protected mice from pains, fever and rash. The majority adenosine analogues. NITD008 death. Mice were also protected (which differs from adenosine by a when treatment was delayed by carbon substitution for N-7 of the up to 24 hours. purine ring and an acetylene group at Importantly, no observed adverse- the 2’ position of ribose) was found effect level could be achieved when to be a potent in vitro inhibitor of rats were dosed orally with NITD008 the DENV RNA-dependent RNA for 1 week. However, toxicity was polymerase (RdRp), inhibiting all observed in rats and dogs treated for four DENV serotypes and signifi- 2 weeks. Experiments are in progress cantly reducing viral titres in various to investigate the cause of toxicity cell lines. The effects of NITD008 and overcome the side effects, were specific to Flaviviridae family although the authors emphasized viruses: it similarly inhibited West that treatment duration would be Nile virus (WNV), yellow fever virus expected to be less than 6 days for and Powassan virus. this acute disease. Using a primer extension-based Together, these data support the RdRp assay, the authors showed that future development of a nucleoside NITD008 inhibited DENV RdRp by inhibitor for the treatment of DENV causing termination of RNA chain infection. Such an approach might synthesis. Importantly, continuous also be broadly effective for the treat- culturing of DENV or WNV ment of other flavivirus infections. in cell lines with NITD008 for up Sarah Crunkhorn to 4 months did not lead to the

emergence of resistant strains. ORIGINAL RESEARCH PAPER Yin, Z. et al. To assess the therapeutic poten- An adenosine nucleoside inhibitor of dengue tial of NITD008, mice were infected virus. Proc. Natl Acad. Sci. USA 16 Nov 2009 (doi: 10.1073/pnas.0907010106) with DENV-2 and immediately