A number of potent inhibitors of helicases encoded by herpes simplex virus, severe

acute respiratory syndrome coronavirus, hepatitis C virus (HCV), West Nile virus (WNV), human papillomavirus and JEV have been reported recently in the scientific literature (Borowski et al., 2002, 2003; Zhang et al., 2003; Bretner et al., 2004a, b, 2005; Ujjinamatada et al., 2007). Some inhibitors BVD-523 cost have been demonstrated to decrease viral replication in cell culture and animal models (Frick & Lam, 2006). Most JEV NS3 helicase/NTPase inhibitors belong to two chemical classes: ring-expanded ‘fat’ nucleosides and nucleotides 1–2 (Zhang et al., 2003) or benzimidazoles and benzotriazoles 3 (Borowski et al., 2003; Bretner et al., 2005) (Fig. 2). The first class may be treated as close

analogs of nucleosides and nucleotides. As these inhibitors are similar to the natural NS3 helicase/NTPase ligand, ATP, they are very likely to compete with ATP for the same binding site. Benzimidazoles and benzotriazoles as well as some naturally occurring compounds such as antibiotic nogalamycin 4 are modulators that interact with the allosteric binding site (Borowski et al., 2002, 2003). The mechanism of their modulating TAM Receptor inhibitor effect remains unclear. However, it may be speculated that the second binding site, which could be occupied by a nucleotide, nucleoside and even by nucleotide base, probably fulfils a regulatory function with respect to the NTPase and/or helicase activities of the enzyme (Borowski et al., 2002). The research presented provides for the first time potential competitive JEV NS3 helicase/NTPase inhibitors that are structurally distinct from nucleosides and their analogs. The design of medicinal substances constituting prototypes

of anti-JEV drugs raises at least three important concerns: first, whether there is a need for anti-JEV therapy if several vaccines against JE are available; secondly, the possibility of laboratory diagnosis before application of anti-JEV drugs; and last but not least, whether the Thalidomide designed compounds are capable of reaching the central nervous system, which will be discussed later. Indeed, the main pillar of JE control is the use of a live attenuated vaccine for humans, developed about 40 years ago (Igrashi, 2002). Although currently available JE vaccines are relatively safe and effective, the drawback is that multiple doses are required. Furthermore, effective delivery of the vaccines to poor communities remains a formidable challenge and compliance and delivery costs have to be considered (Erlanger et al., 2009).