Flavivirus

Basic information and current topics regarding Flaviviridae

Anthracene-based inhibitors of dengue virus NS2B-NS3 protease

When looking through current flavivirus research, it appears that a main interest lies in understanding the dengue virus (DENV) in an effort to develop effective antivirals and/or vaccines. As mentioned in the ‘medical Relevance’ page of this website, the CDC reported just over 900,000 individuals in the US alone were infected with DENV in 2007! Currently, no vaccines exist to prevent this virus from infecting people. There are also no antivirals targeted to treat patients who are already infected with Dengue.  Since dengue can lead to severe, life-threatening complications (i.e. dengue hemorrhagic fever), it is clear to see the significance of developing vaccines/antivirals for this virus.

A 2011 study conducted by Tomlinson, S., et al set out to determine if inhibition of the type 2 dengue virus (DEN2V) NS2B-NS3 protease complex, using an anthracene-based inhibitor could stop viral replication1. This complex functions in viral replication, so development of an antiviral that is capable of targeting and inhibiting this may potentially be a huge accomplishment and a great step forward in decreasing the prevalence of this virus!

The authors of this study had previously determined that two compounds were capable of inhibiting replication of DEN2V (in vitro, via inhibition of the protease complex) and preventing DEN2V replication in cell culture2.  In this current paper, they purchased 24 analogs of one of those compounds, ARDP0006, in an effort to gain a better understanding of how this compound was leading to inhibition of viral replication. By looking at how each analog reacted with the DENV, they could determine which structural properties were important in the mechanism of viral inhibition, as well as rule out certain molecular characteristics that did not function to block viral replication.

Kinetic analysis of each analog was done with the purpose of determining how capable each was at inhibiting, and whether they were acting as competitive or non-competitive inhibitors. After analyzing the 24 analogs, they determined a structural activity relationship (SAR) of the activity of the analogs compared to ARDP0006 in terms of replication inhibition.  After that, they chose 4 more analogs to perform a second round of testing in order to validate that their SAR was accurate. The results of this experiment indicate that the 6A62 analog showed a 60-fold increase in its ability to competitively inhibit the DENV2 NS2B-NS3 protease complex! The authors suggest that an anthracene-based analog inhibitor may function at a much more efficient rate in terms in blocking DENV replication.  They also stated that since this type of inhibitor interacts with conserved regions of flavivirus amino acid residues, this may even be a promising potential avenue in steps toward developing antivirals for other subtypes of the Flaviviridea family, such as West Nile and JEV1!

This is a very exciting paper! Although there is still a long way to go before an antiviral is ready for distribution, it is encouraging to see such a great improvement in the understanding of mechanisms behind specific molecules and there ability to stop flavivirus replication!

References

1. Tomlinson, SM., Watowich, S. (2011).  Anthracene-based inhibitors of dengue virus NS2B-NS3 protease. Antiviral Research. 89: 127-135

2. Tomlinson, SM., Malstrom, RD., et al. (2009).  Structural-based discovery of dengue virus protease inhibitors. Antiviral Research. 82(3): 110-14

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