STUDIES WITH SYNTHETIC NEURAMINIDASE SUBSTRATES

这项申请的目标之一是继续我们对 流感病毒在自然界中的遗传变异及其影响因素 人类和动物的进化。具体地说，我们计划分析 人甲型流感病毒核蛋白基因的分离 在五十多年的时间里。我们还将研究 来自禽类和马类的甲型流感病毒(基因) 以确定它们相对于人类菌株的遗传稳定性。 此外，对流行病学的持续分子分析 重大的甲型、乙型和丙型流感病毒正在规划之中。进一步的目标 关注受体结合/受体破坏的分析 冠状病毒的活动。最近，我们发现， 冠状病毒--如C型流感病毒--识别O-乙酰化 唾液酸(神经氨酸)作为细胞受体，并拥有唾液酸- O-乙酰酯酶作为受体破坏酶。我们现在计划 克隆人类负责这些活动的基因 冠状病毒和我们希望确定的基本特征 蛋白质中的催化和底物结合部位。我们也 计划通过使用以下物质来确定催化机理 特定的酯酶底物和酯酶抑制剂。化合物 后一种可能在抑制病毒复制方面有效 这可能代表了一种新的抗病毒靶向方法 关于携带酯酶的病毒(破坏受体) 活动。我们还计划进一步确定冠状病毒的特征 我们希望确定允许细胞上的受体 (修饰)唾液酸是靶标上唯一的受体分子 细胞。最后，我们希望探讨受体结合的概念 以及属于其他种类的病毒中的受体破坏活性 病毒群。

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.