Identification of High Affinity Ligands against Dengue Virus NS1 for the Development of an Affordable Point-of-Care Diagnostic Kit

Identification of High Affinity Ligands against Dengue Virus NS1 for the Development of an Affordable Point-of-Care Diagnostic KitPublic Health

ABOUT THE PROJECT

This project will lead to early diagnosis of dengue fever so that treatment can occur much quicker for infected patients.

NOTABLE ACHIEVEMENTS (October 2016)

• Computational models for the Dengue Virus (DENV) NS1 protein have been created
• A number of NS1-binding small molecules have been characterized and are now being examined for integration into the chromatographic strips needed for the rapid diagnostic test

PROJECT UPDATE (April 2016)

All computational models for the Dengue virus (DENV) NS1 protein, both in its monomeric and dimeric forms have been generated. From these models, researchers have identified druggable binding sites and the first round of in silico screening predicted a number of small molecules that will bind to these sites. The small molecules have been purchased and interaction with recombinant DENV NS1 protein will be tested using a variety of in vitro assays.

RESEARCH ABSTRACT

Dengue is the most prevalent mosquito-borne viral infection worldwide and is the leading cause of illness and death in tropical/subtropical areas (>390 million people are infected). There are no approved vaccines or drugs against the virus. While most infections resolve without medical intervention, a significant fraction of dengue patients develop hemorrhagic fever and shock syndrome, which if untreated can be fatal. Early supportive care is critical for management of the fever and maintaining the blood volume during hemorrhage. Because the initial symptoms of dengue are similar to many other mosquito transmitted viral infections, early and accurate diagnosis of the disease is critical for these patients.

Generally, current dengue virus assays are not sensitive enough, too expensive and/or time-consuming resulting in delayed/misguided medical intervention in up to 50% of cases. In developing countries, the ease of access, availability of required infrastructure and the cost of diagnosis are usually prohibitive. As such, the need for efficient low-cost diagnostic tools is urgent.

The viral glycoprotein NS1 is an ideal diagnostic marker because it can be detected in patient sera at the same time as symptoms develop. Unfortunately, current NS1-based assays vary greatly in their capacity to detect different dengue serotypes and secondary infections that can progress to hemorrhagic shock. To overcome these problems we will develop pan- and serotype-specific, high-affinity small molecules targeting the NS1 protein for accurate diagnosis of dengue infection. These small molecule ligands will be more stable, affordable and efficient for detecting dengue infection compared to current antibody-based diagnostic kits.