Molecular targets for flavivirus drug discovery

Abstract

Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research.

Figure 1

Schematic representation of flavivirus genome organization and polyprotein processing. The 11 kb positive-sense, single-stranded RNA genome contains a single open reading frame which encodes 3 structural proteins (capsid (C), precursor membrane (prM) and envelope (E)) and 7 non-structural proteins (NS1-NS2A, NS2B, NS3, NS4A, NS4B, NS5). The open reading frame is flanked by untranslated regions. Sites of polyprotein cleavage mediated by the viral NS2B-NS3 and by host signalase and furin are shown, and the enzymatic activities of NS3 and NS5 are also indicated. See text for further information. (Courtesy of Pei-Yong Shi).

Figure 2

The flavivirus replication cycle. Virions bind to cell-surface attachment molecules and receptors and are internalized through endocytosis. In the low pH of the endosome, viral glycoproteins mediate fusion of the viral and cellular membranes, allowing disassembly of the virion and release of its RNA into the cytoplasm. The viral RNA is translated into a polyprotein that is processed by viral and cellular proteases. Viral non-structural proteins then replicate the genomic RNA. Virion assembly occurs at the ER membrane. Capsid protein and viral RNA are enveloped by the membrane and its embedded glycoproteins to form immature virus particles, which are then transported through the secretory pathway. In the low pH of the trans-Golgi network (TGN), prM is cleaved by furin. Mature virions are then released into the cytoplasm. See text for further information. (Courtesy of Rushika Perera and Richard Kuhn.)