STUDIES WITH SYNTHETIC NEURAMINIDASE SUBSTRATES

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One of the goals of this application is to continue our studies on the genetic variation of influenza viruses in nature and their evolution in man and in animals. Specifically, we plan to analyze the nucleoprotein (NP) genes of human influenza A viruses isolated during a period of more than five decades. We will also study influenza A viruses (genes) from the avian and equine populations to determine their genetic stability relative to human strains. Also, a continuing molecular analysis of epidemiologically significant influenza A, B and C viruses is planned. Further goals concern the analysis of the receptor-binding/receptor-destroying activities of coronaviruses. Recently, we found that coronaviruses--like influenza C viruses-recognize O-acetylated sialic (neuraminic) acids as cell receptors and possess a sialate- O-acetylesterase as receptor-destroying enzyme. We now plan to clone the genes responsible for these activities in human coronavirus and we hope to identify the essential features of the catalytic and substrate binding sites in the proteins. We also plan to determine the mechanism of catalysis through the use of specific esterase substrates and esterase inhibitors. Compounds of the latter type may be effective in inhibiting virus replication and could represent a new approach to antiviral targeting with respect to viruses carrying an esterase (receptor-destroying) activity. We further plan to characterize the coronavirus receptors on permissive cells and we hope to determine whether (modified) sialic acids are the sole receptor molecules on target cells. Finally, we hope to explore the concept of receptor-binding and receptor-destroying activities in viruses belonging to other virus groups.