New inhibitors for the dengue virus
07 Sep 2016
Drug repurposing: augmenting the drug discovery pipeline for dengue
N-Desmethylclozapine, Fluoxetine and Salmeterol inhibit dengue infection
Dr Guruprasad Medigeshi, Intermediate Fellow, Translational Health Science and Technology Institute
As per the recent estimates, close to 60 million symptomatic dengue cases occur every year and the overall economic burden of dengue is nearly US$ 9 billion. Vaccine development efforts have resulted in the introduction of first ever dengue vaccine for human use in many countries and other promising vaccine candidates are in advanced stages of clinical trials. Nevertheless, there is lack of significant progress in antiviral development for dengue virus. A number of compounds have been identified as dengue inhibitors using in vitro and in silico approaches but no compounds have advanced to clinical trials in humans and proven to be effective. Repurposing drugs is one way of fast-tracking antiviral discovery as it builds on the pre-existing knowledge of the candidate drug. In cases where the drug has been proven to be safe for human use in other conditions, this process helps to bring the drug to human use faster than a new candidate drug, which, as per the industry estimates, takes 12-15 years from discovery to therapeutic use.
We screened the library of 1280 pharmacologically active compounds (LOPAC1280) for anti-dengue activity. LOPAC1280 covers most major pharmacologically relevant target classes and many of them are approved as drugs for human use, thus providing an excellent platform for repurposing as antivirals. In our study, we used an imaging-based screening approach to screen LOPAC1280 for dengue inhibitors. We identified three inhibitors that specifically blocked early stages of dengue viral RNA replication. Our data suggest that treatment with the three dengue inhibitors, N-Desmethylclozapine, Fluoxetine and Salmeterol, leads to alteration in the autophagosome/lysosome biogenesis affecting early stages of DENV life-cycle. Our data further underscores the value and economic benefits of drug repositioning efforts that could be harnessed to augment the antiviral pipeline.
Medigeshi GR, Kumar R, Dhamija E, Agrawal T, Kar M. N-Desmethylclozapine, Fluoxetine and Salmeterol inhibit post-entry stages of dengue virus life-cycle. Antimicrobial Agents and Chemotherapy. 2016. doi: 10.1128/aac.01367-16.
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Banner Image Credit : Liverpool School of Tropical Medicine courtesy of A Stich, Wellcome Images
Aedes albopictus adult: This picture shows a female Ae. albopictus mosquito biting. Ae. albopictus is a vector for various infections, especially dengue fever.