STUDIES WITH SYNTHETIC NEURAMINIDASE SUBSTRATES

本申请的目标之一是继续我们的研究 自然界中流感病毒的遗传变异及其 人类和动物的进化。 具体来说，我们计划分析 分离的人A型流感病毒的核蛋白（NP）基因 在五十多年的时间里。 我们还将研究 来自禽类和马种群的甲型流感病毒（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 计划进行重大的甲型、B和丙型流感病毒。 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--像C型流感病毒一样--识别O-乙酰化 唾液酸（神经氨酸）作为细胞受体，并具有唾液酸- 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，我们希望能确定的基本特征， 蛋白质中的催化和底物结合位点。 我们也 计划通过使用催化剂来确定催化机制， 特异性酯酶底物和酯酶抑制剂。 化合物 后一种类型的药物可能有效抑制病毒复制 并可能代表一种新的抗病毒靶向方法， 关于携带酯酶的病毒（受体破坏） 活动 我们计划进一步描述冠状病毒的特征 我们希望能确定 （修饰的）唾液酸是靶向的唯一受体分子。 细胞 最后，我们希望探讨受体结合的概念 和受体破坏活动的病毒属于其他 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.