New Approaches to Structure-Based Discovery of Dengue Protease Inhibitors

Abstract

Dengue virus (DENV), a member of the family Flaviviridae, presents a tremendous threat to global health since an estimated 2.5 billion people worldwide are at risk for epidemic transmission. DENV infections are primarily restricted to sub-tropical and tropical regions; however, there is concern that the virus will spread into new regions including the United States. There are no approved antiviral drugs or vaccines to combat dengue infection, although DENV vaccines have entered Phase 3 clinical trials. Drug discovery and development efforts against DENV and other viral pathogens must overcome specificity, efficacy, safety, and resistance challenges before the shortage of licensed drugs to treat viral infections can be relieved. Current drug discovery methods are largely inefficient and thus relatively ineffective at tackling the growing threat to public health presented by emerging and remerging viral pathogens. This review discusses current and newly implemented structure-based computational efforts to discover antivirals that target the DENV NS3 protease, although it is clear that these computational tools can be applied to most disease targets.

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

“…The DENV genome, a positive-sense single-stranded RNA, encodes a single poly-protein precursor that consists of three structural proteins (C, M, and E) and seven nonstructural 1127 www.chinaphar.com Wu DW et al Acta Pharmacologica Sinica npg proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Previous studies have shown that NS3 contains two functional domains: a serine protease at the N-terminus and an RNA helicase at the C-terminus [12][13][14] . NS2B is an essential element that acts as a co-factor to greatly enhance the activity of NS3 by 3300-to 6600-fold [15,16] .…”

“…As a viral protease complex, NS2B/ NS3 is mainly in charge of cleaving the viral poly-protein precursor to generate structural proteins and nonstructural proteins, and the disruption of NS2B/NS3 protease function distinctly inhibits viral replication [17] . Therefore, the NS2B/ NS3 protease is considered as an attractive target for anti-DENV drug development [14] . In fact, the treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections serve as successful precedents for targeting key viral proteases [18][19][20] .…”

Molecular dynamic simulation of complex NS2B-NS3 DENV2 protease with potential inhibitors of cyclic tripeptide

“…Dengue virus (DENVs) comes from the family Flaviviridae, and genus Flavivirus (Tomlinson et al, 2009). Dengue virus is transmitted by Aedes mosquitoes through their bites.…”

“…serotypes infection, but may increase the pathogenicity of subsequent infection by the three other serotypes (Tomlinson et al, 2009). Intial infection of dengue virus has caused the death rate of about 5%, and increase to 40% if a virus infection continues to progress until the dengue shock syndrome (DSS) (Tambunan et al, 2009).…”

“…Some examples of nonstructural (NS) enzymes of the replication complex is a cofactor of NS2B-NS3 protease, NS3 helicase / nucleoside triphosfatase (NTPase) / RNA 5 'triphosfatase (RTPase), and NS5 methyltransferase / RNA-dependent RNA polymerase (RdRp). These proteins can be used as potential inhibitor targets for antiviral agents during virus replication (Tomlinson et al, 2009). NS3 protease enzymes are the primary targets for the development of antiviral drugs since dengue NS2B-NS3 protease is required for viral replication (Othman et al, 2007).…”