Anticancer Drugs Repurposed for Dengue - A Promising Breakthrough in Dengue Fever Treatment
“We sympathise with all the families who have suffered the loss of a child,” expressed a spokesperson from Sanofi Pasteur, the French multinational pharmaceutical company, upon the deaths of school-age children in the Philippines after being administered Sanofi’s dengue virus vaccine, Dengvaxia. Notably, no deaths had been reported during more than a decade-long clinical trials of the world’s first dengue vaccine. However, in November 2017, Sanofi disclosed that Dengvaxia “might increase the risk of severe disease in people who had never been exposed to the virus.
Despite extensive efforts, current dengue prevention strategies, including vaccinations, have significant limitations, leaving no specific treatment for dengue fever. This vector-borne disease, primarily affecting Asia, is transmitted by infected mosquitoes (vectors) that carry and transmit the dengue virus from person to person, causing severe fever.
Could undercounted infections explain the lack of attention to dengue’s severity?
A 2013 study published in Nature estimated the true total of infections to be more than three times the estimate of the World Health Organisation.
The traditional approach of developing new drugs from scratch can be both time-consuming and expensive. Therefore, researchers at SBASSE (Syed Babar Ali School of Science and Engineering) have pursued an alternative strategy known as drug repurposing. This approach involves identifying existing drugs that might be effective against diseases different from their original intended use. In this study, led by Hafiza Nosheen Saleem under the supervision of Dr Muhammad Saeed, a library of 1127 small molecules, initially designed as antivirus drugs, were screened to determine their potential efficacy against the dengue virus.
Nosheen and Dr Saeed, alongside their collaborators Summara Kousar, Ammar Hassan Jiskani, Iqra Sohail and Dr Amir Faisal, focused their efforts on a specific protein within the dengue virus known as DENV NS2B/NS3 protease. This protein plays a crucial role in the virus's life cycle, and inhibiting it could disrupt the virus's ability to replicate. Four molecules in the screen library, ABT263, ABT737, AT101 and TW37, demonstrated promise as inhibitors of the NS2B/NS3 protease. These molecules were initially developed as inhibitors for B-cell lymphoma 2 (Bcl-2), a member of the protein family. Notoriously associated with the survival of certain types of cancer cells, Bcl-2 plays a key role in aiding cancer cells to withstand chemotherapy. For instance, ABT263 is currently being tested for the treatment of high-grade triple-negative breast cancer and ovarian cancer.
To assess the effectiveness of these molecules in inhibiting the NS2B/NS3 protease, the researchers employed a metric called IC50, representing the "half-maximal inhibitory concentration." This metric gauges how effectively a molecule can inhibit the protease. Further analysis of these molecules' inhibition mechanisms revealed that ABT263 and ABT737 competitively inhibited the protease by binding to the same site as the target substrate. In contrast, AT101 and TW37 were identified as non-competitive inhibitors, binding to a different site and inducing changes in the enzyme's structure or activity.
The study suggests that the identified inhibitors have the potential to be developed into specific anti-dengue therapeutics. This is a promising avenue for further research and development, as these molecules have already undergone testing for their safety and pharmacological properties as anticancer drugs. With the aim of preventing tragic incidents like the loss of school-age children to dengue in the Philippines, this research provides hope for improved treatments and enhanced protection against this mosquito-borne disease.