STUDY ON THE MECHANISM OF HOST RANGE VARTIATION OF INFLUENZA VIRUSES AND APPLICATION TO THE DEVELOPMENT OF ANTI-INFLUENZA DRUG

本课题的目的是通过对流感病毒受体唾液糖链的研究，揭示流感病毒宿主范围变异的机制，为开发针对流感病毒不同抗原变异株的抗流感病毒药物奠定基础。在两个预算年度中，获得了以下结果：1）鉴定了人、禽、猪和马流感病毒受体的共同结构。2）流感病毒通过选择与宿主细胞受体分子中唾液酸的结合特异性和唾液酸的分子种类来完成进化; 3）流感病毒血凝素中的226号氨基酸被发现对宿主细胞受体中2- 3、2 -6唾液酸键的识别具有关键性，226 Leu识别2-6，而226 Gln识别2-3。4）发现一些非唾液酸糖链能有效地结合从人、禽和猪宿主分离的流感病毒。这些结果表明这些糖脂具有作为人和动物流感病毒的第二共同受体分子的功能。5）发现含有唾液酸乳糖系列糖链的高分子量聚合物作为人和动物流感病毒的非常有效的抑制剂，表明这些化合物可作为种子化合物用于开发抗-对流感病毒的所有抗原变异体有效的流感药物。上述新结果表明，该项目的目标取得了令人满意的进展，本项目取得了开发对流感病毒所有抗原变异体有效的抗流感新药的基础性实验结果。

The aim of this project is to elusidate the mechanism of host range variation of influenza viruses and to establish the fundamental idea for the developing the anti-influenza drug effective to every different antigenic variants of influenza viruses through the study on receptor sialosugar chains. During two budget yearts, following results were obtainbed.1)The common structures of the receptor for human, avian, swine, and equine influenza viruses were identified. These have the neutralizing activity for the viruses.2)The influenza viruses accomplish the evolution by the selection of the binding specificity to the sialyl linkage and molecular species of sialic acid in the receptor molecules on host cells.3)The amino acid No.226 in the hemagglutinin of influenza viruses is found to be clitical for the recognition of 2-3,2-6 sialyl linkage in host cell receptor, 226Leu recognizes 2-6, but 226Gln 2-3, respectively.4)It was found that some non-sialyl sugar chains are effective to bind to influenza viruses isolated from human, avian, and swine hosts. These results indicate that these glycolipids have a function as the second common receptor molecule for human and animal influenza viruses.5)High molecular weight polymers containing sialyllacto-series sugar chains were found as a very effeftive inhibitor for human and animal influenza viruses, indicating that these compounds can be used as a seed compounds to develope anti-influenza drugs effective to all antiugenic variants of influenza viruses.The above new results show that the aim of this project is satisfactory progressed, and the fundamental experimantal results to develope new anti-influenza drugs effective to all antigenic variants of influenza viruses are obtained in this projects.