However, the subsequent formation of double stranded RNA intermediates is a strong trigger of innate immune responses. morphological appearance (Weiss and Navas-Martin, 2005). Their genome is the largest RNA genome to date and packaged together with the nucleocapsid protein, several membrane proteins (M, E and sometimes a hemagglutinin esterase protein) and the spike protein. Translation of the replicase gene produces two large poly-proteins with diverse enzymatic activities needed for efficient replication. A phylogenetic analysis of the replicase gene, using a distantly related torovirus as an outgroup, demonstrated that three groups of coronaviruses can be distinguished and that despite a number NKY 80 of unique features, severe acute respiratory syndrome coronavirus (SARS-CoV) is most closely NKY 80 related to group 2 coronaviruses (Snijder et al., 2003). Viruses that belong to group1 include transmissible gastroenteritis virus of pigs, feline infectious peritonitis virus of cats and the human coronaviruses 229E and HCoV-NL63 (Fig. 1 ). In group 2, viruses such as murine hepatitis virus, bovine coronavirus, human coronavirus OC43, HKU1 and SARS-CoV are classified. Group 3 constitutes only avian coronaviruses, such as infectious bronchitis virus and turkey coronavirus. Each of the three groups of viruses classified thus far encodes a set of unique small proteins with unknown functions. Coronaviruses cause acute and chronic respiratory, enteric and or central nervous system diseases in many species, including humans (Weiss and Navas-Martin, 2005). Until recently, the need to develop antiviral drugs was limited because human coronaviruses like 229E and OC43 only cause a mild disease in humans. The burden of disease for HCoV-NL63 and HKU1 are not known at present. However, the emergence of SARS changed this picture. In this review we discuss the latest developments in antiviral drug testing specifically with regard to SARS-CoV and whenever applicable we broaden the scope to other coronaviruses. A range of compounds may interfere with the lifecycle of SARS-CoV as shown in Fig. 2 and discussed below. Open in a separate window Fig. 1 Phylogenetic tree based on deduced amino acid sequences of the coronavirus replicase ORF1b gene for bovine coronavirus (BCoV), human coronavirus 22E (HuCoV-OC43), mouse hepatitis virus (MHV), SARS-CoV, infectious bronchitis virus (IBV), transmissible NKY 80 gastroenteritis virus (TGEV), feline infectious peritonitis virus (FIPV), porcine epidemic diarrhea virus (PEDV), human coronavirus 229E (HuCoV-229E), human coronavirus NL63 (HuCoV-NL63) and Berne Torovirus (used as an outgroup). Open in a separate window Fig. 2 Schematic overview of the SARS-CoV lifecycle and inhibitors of viral replication. 2.?SARS The 2002C2003 SARS outbreak affected more than 8000 individuals worldwide and caused 774 fatalities (Poon et al., 2004). The lung pathology of fatal SARS showed bronchial epithelial denudation, diffuse alveolar damage and type-2 pneumocyte hyperplasia. In patients who died late in the course of the disease, also syncytial cells were seen in the alveoli. Subsequently, three laboratories independently reported the isolation of a novel coronavirus from clinical specimens of SARS patients (Drosten et al., 2003, Peiris et al., 2003, Ksiazek et al., 2003). The virus was visualized by electron microscopy and identification of the virus was accomplished through sequencing of different fragments of the replicase gene, obtained by random-priming RT-PCR and coronavirus consensus primers. Most importantly, SARS-CoV was detected in lung biopsies and bronchoalveolar lavage of SARS patients using virus culture, RT-PCR, and electron microscopy, whereas viral antigen was detected in alveolar epithelial cells and macrophages by immunohistology (Nicholls et al., 2006). To further establish SARS-CoV as the cause of the disease, Koch’s postulates were fulfilled by reproduction of the disease in a relevant animal model. Infection of cynomolgous macaques with SARS-CoV led to disease that was pathologically similar to Rabbit polyclonal to AKR1D1 that seen in human patients with SARS, with epithelial necrosis, serosanguinous alveolar exudates, hyaline membranes, type-2 pneumocyte hyperplasia, diffuse alveolar damage and the presence of syncytia (Fouchier et al.,.