Introduction Rotavirus RV a member
Rotavirus (RV), a member of Reoviridae family, is a non-enveloped virus which has a double-stranded RNA genome of 11 segments surrounded by three concentric protein layers. It has been reported to cause estimated 25% of moderate-to-severe illnesses (Kotloff et al., 2013) and 30% of total diarrheal deaths during the first 2 years from birth (Wang et al., 2016a). The development and deployment of rotavirus vaccines was a breakthrough in the fight against diarrheal diseases. Two rotavirus vaccines, Rotarix™ and Rotateq, are licensed and widely available in several countries (Yin et al., 2018). Nevertheless, due to limited resources, developing countries including India, Nigeria, Pakistan, Ethiopia and the Democratic Republic of the Congo bear the major burden of mortality (Groome et al., 2014). In addition, immunocompromised patients are also under the risk of RV infection which would cause remarkable morbidity and mortality (Lee and Ison, 2014; Sugata et al., 2012; Yin et al., 2015c). For the treatment of rotavirus gastroenteritis, intravenous fluid supply has been used for treatment of dehydration from diarrhea. However, in the severe case of inpatients and immunocompromised patients who are suffering from prolonged diarrhea and fever, virus-specific treatment will be expected, if possible. In fact, there is still no FDA-approved medication available against rotavirus disease. Therefore, to ensure that the remaining burden of mortality and morbidity can be fully addressed in the future, research on the development of novel antiviral strategies is highly needed.
Cellular nucleotides, composed of purines and pyrimidines, play a vital role in constituting nucleic acids RNA and DNA. De novo synthesis and salvage pathway are the two pathways for nucleic leukotriene receptor antagonists synthesis in vivo (Evans and Guy, 2004). Viral replication heavily relies on host supply of nucleoside biosynthesis. Therefore, host enzymes involved in nucleoside biosynthesis represent potential targets for antiviral development. Ribavirin, the most well-known antiviral drug, is such an inhibitor that suppresses guanine biosynthesis via inhibition of cellular IMP dehydrogenase (IMPDH). Several studies have indicated that depletion of cellular GTP pool is the primary mechanism by which ribavirin inhibits virus replication (e.g. flaviviruses and hepatitis E virus) (García et al., 2018; Nicolini et al., 2018). Along this line, we aim to investigate whether inhibitors of the pyrimidine biosynthesis pathway could be targeted for potential antiviral development against rotavirus.
Dihydroorotate dehydrogenase (DHODH) is sequentially the fourth and the rate-limiting enzyme in the de novo biosynthesis pathway of pyrimidines. It is located in the inner membrane of mitochondria, where it plays a role of converting dihydroorotate to orotate (Munier-Lehmann et al., 2013). Then, the multifunctional UMP synthase uses orotate to produce UMP, one of the essential precursors for synthesis of all other pyrimidine nucleotides. Several studies have reported that inhibition of DHODH enzyme suppresses a range of different viruses replication (Hoffmann et al., 2011; Luthra et al., 2018; Tan et al., 2005; Wang et al., 2011, 2016b).
Materials and methods
Discussion Though rotavirus vaccine has been introduced, and the vaccine remarkably reduced the burden of rotavirus gastroenteritis in many developed countries, however, due to prevalence and diversity of the virus, one third to half of the children are still suffering from vaccination failure in some developing countries (Macartney et al., 2000). Antiviral treatment shall serve as complement to vaccine. A drug repurposing approach offers many advantages for the identification of new antiviral strategies over the development of new drugs, since safety and pharmacology in humans are already well known. Therefore, if a drug, currently in clinical use, demonstrates considerable antiviral activity against rotavirus, there should be great potential to expand its application to combating rotavirus infection.