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  • Of note BRQ and LFM are two well known immunosuppressive


    Of note, BRQ and LFM are two well-known immunosuppressive agents (Batt, 1999). As for LFM, it was reported as immunosuppressive therapy for bone marrow (Avery et al., 2004) and renal (Chon and Josephson, 2011) transplantation. Accumulating evidence indicated that organ transplant patients irrelevant to their ages are more vulnerable to rotavirus infection. Thus, the potential clinical prospects of BQR and LFM or their analogues may be of achieving “one stone two birds” effects: exerting immunosuppressive function and anti-rotavirus effect at the same time. Of note, BQR was reported to have some side effects, such as leukocytopenia,thrombocytopenia, reduced body weight gain or body weight loss, thymic atrophy, cellular depletion of bone marrow and splenic white pulp, and villous atrophy in jejunum (Pally et al., 1998). Similarly, LFM also has side effects, including gastrointestinal symptoms, rash or allergic reactions and alopecia (Emery et al., 2000; Mladenovic et al., 1995; Smolen et al., 1999; Strand et al., 1999). These kinds of clinical observation are comprehensible based on the fact that all drugs come with side effects. Importantly, the drug dosages of both drugs used in our study for inhibition of rotavirus are much lower than their previous clinical trial dosages (Maroun et al., 1993; Natale et al., 1992; Smolen et al., 1999). This might make BQR or LFM a preferable option for treating rotavirus infection, achieving high efficacy with less side effects. In addition, pyrimidine biosynthesis (Fig. 7B) represents a potential host pathway for novel antiviral drug development. These specific inhibitors of this pathway may represent as a starting point for the development of efficient anti-rotavirus drugs with more broad applications. Intestinal carcinoma-derived cell lines such as Caco2 cell line are widely used as in vitro model to investigate rotavirus infection (Cuadras et al., 2002; Frias et al., 2012). Compared to such two-dimensional (2D) single cell type culture systems, the three-dimensional (3D) model of human primary intestinal organoids surpass 2D models by cell WAY-600 and spatial structure on rotavirus infection (Yin et al., 2015a). Specifically, these primary intestinal organoids consist of many undifferentiated and heterogeneous cell types with similar functions as in the organ/tissue of origin (Sato and Clevers, 2012, 2013; Sato et al., 2009, 2011), including enterocytes, enteroendocrine cells, goblet cells, Paneth cells and stem cells (Saxena et al., 2015). We have validated our results observed in conventional cell culture model also in the primary human organoids. Moreover, the use of rotavirus strains isolated from clinical samples leads our study one step closer to clinical therapy against rotavirus infection. Nucleotides play an important role in host cell metabolism and are essential for virus infection. Many inhibitors targeting de novo pyrimidine biosynthesis (Fig. 7B) have been well studied on dengue virus, HBV, HEV and other virus infection models (Beardsley et al., 1989; Greene et al., 1995; Hoppe-Seyler et al., 2012; Nelson et al., 1975; Qing et al., 2010; Silva et al., 1997; Wang et al., 2011, 2016b). In this study, we demonstrated that both BQR and LFM, inhibitors of DHODH enzyme, have potent antiviral activity against rotavirus infection. Mechanistic study demonstrated that BQR and LFM exert their anti-rotavirus effect through targeting DHODH to deplete pyrimidine nucleotide pool. Therefore, targeting pyrimidine biosynthesis represents a potential approach for developing antivirals against rotavirus.
    Conflicts of interest
    Introduction Despite the advance of pathway-targeted therapeutics, KRAS mutant cancers still remain a largely unmet medical need. The prevalence of activating KRAS mutations is particularly high (greater than 90%) in pancreatic ductal adenocarcinoma (Bardeesy and DePinho, 2002), which has a notoriously poor prognosis. KRAS mutations are also prevalent WAY-600 in lung and colon cancers, and the presence of these mutations negatively impacts therapeutic efficacy (Linardou et al., 2008). While direct targeting of the KRAS protein has shown renewed promise (Hunter et al., 2014, Ostrem et al., 2013, Sun et al., 2012), KRAS inhibitors have not yet entered the clinic. Synthetic lethality screens have frequently been used to find alternative points of intervention in mutant KRAS-driven cancers, but the results of these screens have not yet been translated to clinical benefit.