The overall objective of this contract is to provide a resource for preclinical in vitro evaluation of new antiviral agents against respiratory viruses. All compounds will be screened for their cytotoxicity to human HeLa, mouse L929 and Madin Darby canine kidney (MDCK) cells, and for their antiviral activity against a panel of viruses, including influenza A and B viruses, respiratory syncytial virus (RSV), parainfluenza type 3 (Para 3) virus, and adenovirus type 5. In the initial screen for toxicity, inhibition of cell growth in subconfluent monolayers of tissue cells will be used. Primary screening for antiviral activity will utilize plaque reduction and inhibition of cytopathic effect. Further testing of active compounds will be performed to determine the level of cell toxicity (i.e., DNA, RNA, or protein synthesis inhibition) and the mechanism of antiviral activity (i.e., viral RNA transcription, uncoating). When results warrant, additional studies such as testing the experimental drug in combination with other compounds for toxicity and antiviral efficacy, testing in some detail to determine which step(s) of virus replication are inhibited by the test compound, or testing methods to reduce cell toxicity will be performed.
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