Most of the emerging and/or neglected viral pathogens have an RNA genome, including viruses such as the dengue fever virus (and other flaviviruses), Chikungunya virus, enterovirus 71, rabies virus, HEV, coronaviruses and arenaviruses, bunyaviruses and filoviruses. Although it should be very well feasible to develop potent inhibitors against each of the (currently known) neglected and/or emerging viruses, this may economically not be a viable option. and HCV as well as influenza viruses. More than 25 years after the discovery of HIV, over 25 compounds have been formally approved for the treatment of AIDS and most of these are being used in fixed-dose drug combinations. Potent, highly effective and well-tolerated drugs are also available for the treatment of HBV infections. For HCV two protease inhibitors were recently approved and a number of other direct-acting antivirals (DAAs) is in development, they will ultimately be combined in appropriate drug regimes. Potent nucleos(t)ide analogs (such as acyclovir, ganciclovir and cidofovir), that target the viral polymerase, are available for the treatment of herpesvirus infections, yet novel drugs that target the viral helicaseCprimase or the CMV terminase are being developed. For influenza virus, novel neuraminidase inhibitors (such as peramivir and laninamivir octanoate) and a polymerase inhibitor (favipiravir) are in development. The broad-spectrum inhibitor ribavirin is usually approved for the treatment of infections with the respiratory syncytial virus, HCV and Lassa virus. In conclusion, the large number of drugs that are available against HIV (and the many drugs that are in clinical development for the treatment of chronic HCV infections) demonstrates that even for viruses with a short genome, many excellent molecular targets exist for inhibition of viral replication. Yet, for many viruses that cause life-threatening infections in man there are no drugs at hand for treatment. Most of the emerging and/or neglected viral pathogens have an RNA genome, including viruses such as the dengue fever virus (and other flaviviruses), Chikungunya virus, enterovirus 71, rabies virus, HEV, coronaviruses and arenaviruses, bunyaviruses and filoviruses. Although it should be very well feasible to develop potent inhibitors against each of the (currently known) neglected and/or emerging viruses, this may economically not be a viable option. Therefore, ideally, potent and broad-spectrum drugs should be developed that can be used for the treatment of a variety of such viral infections. Possibly, nucleoside analogs with such characteristics may be designed/discovered. An alternative is usually to develop drugs that have broad-spectrum antiviral activity within a given genus or family (e.g., broad-spectrum flavivirus or paramyxovirus inhibitors). It is probable that novel, potentially highly pathogenic RNA viruses will emerge in the future; consider for instance the recent fatalities with the novel coronavirus-EMC [1?]. Having broad-spectrum (pan-genus; pan-family or pan-RNA virus) inhibitors at hand may help to contain such future outbreaks. In this review we will provide a nonexhaustive overview of recent developments in the search for small molecule inhibitors of (some) neglected/emerging RNA viruses. Flaviviruses About two-fifth of the world’s population is now at risk for dengue contamination and 50C100 million cases are estimated to occur worldwide every year [2, 3??]. An estimated 500?000 people with severe dengue require hospitalization each year; a very large proportion of whom are children, resulting in a fatal outcome in about 2.5% of those affected. There is neither vaccine nor a specific antiviral treatment. Likewise, no antivirals are available for the treatment of life-threatening infections with other flaviviruses such as those caused by yellow fever virus [4], Japanese encephalitis virus and West Nile virus. The organization of the genome of flaviviruses resembles??to some extent??that of the related HCV, of which the viral serine protease and the RNA-dependent RNA polymerase have been shown to be excellent targets for inhibition of viral replication (both and in the infected patients) [5]. So far, flavivirus NS3 protease inhibitors with a potency comparable to that of the HCV NS3 protease inhibitors have not yet been identified. Particular differences in the characteristics and structure of the different NS3 proteases may be the reason [6]. An exhaustive review around the flavivirus NS3 protease as Rivastigmine tartrate a target for the design of inhibitors has recently been published [7]. Second, nucleoside as well as non-nucleoside polymerase inhibitors of HCV have been and currently are in clinical development. They exert pan-genotype antiviral activity and have a high barrier to resistance [8]. Nucleoside polymerase inhibitors (that target the enzyme as their 5-phosphorylated metabolite) have also been shown to exert pan-serotype anti-dengue virus activity and in dengue mouse models [9, 10]. Balipiravir,.In a recent press release, Biota reported successful completion Rivastigmine tartrate of a phase IIb study with vapendavir. 2013 1879-6257/$ C see front matter, ? 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.coviro.2013.03.001 Introduction Today, small molecule antiviral drugs are available for the treatment of infections with herpesviruses, HIV, HBV and HCV as well as influenza viruses. More than 25 years after the discovery of HIV, Rivastigmine tartrate over 25 compounds have been formally approved for the treatment of AIDS and most of these are being used in fixed-dose drug combinations. Potent, highly effective and well-tolerated drugs are also available for the treatment of HBV infections. For HCV two protease inhibitors were recently approved and a number of other direct-acting antivirals (DAAs) is in development, they will ultimately be combined in appropriate drug regimes. Potent nucleos(t)ide analogs (such as acyclovir, ganciclovir and cidofovir), that target the viral polymerase, are available for the treatment of herpesvirus infections, yet novel drugs that target the viral helicaseCprimase or the CMV terminase are being developed. For influenza virus, novel neuraminidase inhibitors (such as peramivir and laninamivir octanoate) and a polymerase inhibitor (favipiravir) are in development. The broad-spectrum inhibitor ribavirin is approved for the treatment of infections with the respiratory syncytial virus, HCV and Lassa virus. In conclusion, the large number of drugs that are available against HIV (and the many drugs that are in clinical development for the treatment of chronic HCV infections) demonstrates that even for viruses with a short genome, many excellent molecular targets exist for inhibition of viral replication. Yet, for many viruses that cause life-threatening infections in man there Rabbit Polyclonal to CLCNKA are no drugs at hand for treatment. Most of the emerging and/or neglected viral pathogens have an RNA genome, including viruses such as the dengue fever virus (and other flaviviruses), Chikungunya virus, enterovirus 71, rabies virus, HEV, coronaviruses and arenaviruses, bunyaviruses and filoviruses. Although it should be very well feasible to develop potent inhibitors against each of the (currently known) neglected and/or emerging viruses, this may economically not be a viable option. Therefore, ideally, potent and broad-spectrum drugs should be developed that can be used for the treatment of a variety of such viral infections. Possibly, nucleoside analogs with such characteristics may be designed/discovered. An alternative is to develop drugs that have broad-spectrum antiviral activity within a given genus or family (e.g., broad-spectrum flavivirus or paramyxovirus inhibitors). It is probable that novel, potentially highly pathogenic RNA viruses will emerge in the future; consider for instance the recent fatalities with the novel coronavirus-EMC [1?]. Having broad-spectrum (pan-genus; pan-family or pan-RNA virus) inhibitors at hand may help to contain such future outbreaks. In this review we will provide a nonexhaustive overview of recent developments in the search for small molecule inhibitors of (some) neglected/emerging RNA viruses. Flaviviruses Rivastigmine tartrate About two-fifth of the world’s population is now at risk for dengue infection and 50C100 million cases are estimated to occur worldwide every year [2, 3??]. An estimated 500?000 people with severe dengue require hospitalization each year; a very large proportion of whom are children, resulting in a fatal outcome in about 2.5% of those affected. There is neither vaccine nor a specific antiviral treatment. Likewise, no antivirals are available for the treatment of life-threatening infections with other flaviviruses such as those caused by yellow fever virus [4], Japanese encephalitis virus and West Nile virus. The organization of the genome of flaviviruses resembles??to some extent??that of the related HCV, of which the viral serine protease and the RNA-dependent RNA polymerase have been shown to be excellent targets for inhibition of viral replication (both and in the infected patients) [5]. So far, flavivirus NS3 protease inhibitors with a potency comparable to that of the HCV NS3 protease inhibitors have not yet been identified. Particular differences in the characteristics and structure of the different NS3 proteases may be the reason [6]. An exhaustive review on the flavivirus NS3 protease as a target for the design of inhibitors has recently been published [7]. Second, nucleoside as well as non-nucleoside polymerase inhibitors of HCV have been and currently are in clinical development. They exert pan-genotype antiviral activity and have a high barrier to resistance [8]. Nucleoside polymerase inhibitors (that target the enzyme as their 5-phosphorylated metabolite) have also been shown to exert pan-serotype anti-dengue virus activity Rivastigmine tartrate and in dengue mouse models [9, 10]. Balipiravir, a nucleoside HCV polymerase inhibitor, was evaluated for potential activity in dengue-infected patients. No protective activity was observed [11]. The lack of activity of balipiravir can very probably be ascribed to the very weak potency of.