The underlying mechanism for this pronounced effect of DPP-4 inhibition

concentration of achieved approximately after initiating treatment. CQ has a long elimination phase of about 7 h. The Cmax is,5,300 ng/mL and AUC is 23,000 h*ng/mL. We consider it reasonable to assume that these exposure parameters are needed for CQ to be efficacious in the IP EBOV challenge. The mouse data provide an initial indication of how the CQ concentrations change during the course of the efficacy study and provide a starting point for developing dosage regimens to achieve similar protection in higher animals. To determine the antiviral mechanism of action for CQ and other 4-AQs, a representative set of compounds was tested for impact on virus entry, using a pseudotype virus assay, or wild type virus purchase 529-53-3 genome replication by qRT-PCR. For entry, all enveloped viruses use glycoproteins to fuse the virus and cell membranes together. The virus core is then released into the cell cytoplasm. The function of the GP can be separated from other virus proteins by making a pseudotype, which consists of the GP of a donor virus coated onto a surrogate core particle. This was done using a vesicular stomatitis virus core encoding a luciferase reporter. Dose response curves were produced using each compound and measuring 1432908-05-8 pseudotyped virus reporter activity. For genome replication, a qRT-PCR assay was used to detect relative genome copy number. Both assays for EBOV and MARV were performed with similar outcomes. CQ and related 4AQ antimalarial compounds were less effective against LASV and were not evaluated in follow-up assays. The EC50 of CQ and the related 4AQ compounds were determined and are given in Table 5. Since all compounds impacted the pseudotyped viruses, it is likely that each acts at a common step of virus entry mediated by the EBOV or MARV GP. However, differences were observed in the potency of each compound for inhibition of entry or replication and may reflect the sensitivity of each GP to endosomal pH in triggering membrane fusion. The EC50 values for EBOV and MARV entry were AMD,AQ13