STRUCTURE/FUNCTION OF PROTOZOAN SIALIDASES

原生动物唾液酸酶的结构/功能

• 批准号: 2075008
• 负责人: Mercio A Perrin
• 金额: $ 54.63万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2075008
• 关键词: Trypanosoma cruzi; enzyme activity; enzyme structure; exo alpha sialidase; protein structure function; protozoa

Trypanosoma cruzi is the etiological agent of Chagas, a chronic debilitating incurable disease afflicting millions of people in Latin America. Cryptosporidium parvum causes gastrointestinal illness in both immunocompetent and immunodeficient people, in particular those with AIDS, where infection can be unrelenting and fatal. Both T. cruzi and C. parvum express a protein with sialidase (SA) activity. T. cruzi SA has the ability to transfer sialic acid to galactose acceptors and thus is a trans-sialidase (TS). A large body of evidence suggest that TS is an important mediator of T. cruzi-host interactions, as it promotes trypanosome attachment to mammalian cells and potently enhances virulence in vivo. Cryptosporidium also expresses SA in two infective stages, sporozoites and merozoites. Cryptosporidium SA is immunologically related to the T. cruzi enzyme and it may play role in the genesis of diarrhea. This program project brings together top world experts in various fields with the common goal of upping understanding of the structure and function of the sialidases of T. cruzi and Cryptosporidium. Studies on the biology of TS in mammals will be performed by the principal investigator of New England Medical Center, Boston, the same site where Dr. Honorine Ward will molecularly characterize the cryptosporidium enzyme, which was recently discovered in her laboratory. Biological studies in the insect vector of T. cruzi will be done by Dr. John Edman in the University of Massachusetts, Amherst. Tridimensional structure and kinetic analysis will be carried out by Dr. Garry Taylor at Bath University, England. And synthesis of sialidase inhibitors based in molecular modeling and structural analysis will be performed at Monash University, Australia, by Dr. Mark von Itzstein, who, for the sake of this project, already synthesized sialic acid derivatives that are active against TS. Biological properties of the inhibitors will be assayed in Boston. A Scientific Advisory Committee made of three internationally celebrated authorities in the structure, biology, and molecular biology of carbohydrates and sialic acid-binding proteins (Drs. Don Wiley, Stephen Beverly, and Roland Schauer) will counsel the principal investigator and monitor progress of the proposed research. The committee and the investigators will meet once a year in Boston. Therefore, the program project should provide insights into the structure and biology of the sialidases expressed by parasites that cause two important diseases of mankind. It may also yield a chemotherapeutic agent to treat these diseases, as similar studies lead to the discovery of inhibitors of influenza virus sialidase (by Dr. Itzstein), currently in clinical trials in many parts of the world, including the United States.

克氏锥虫是慢性支气管炎查加斯的病原体 令人衰弱的不治之症在拉丁语中折磨着数百万人 美国。微小隐孢子虫引起两种疾病的胃肠道疾病 免疫能力和免疫缺陷的人，特别是那些患有 艾滋病，那里的感染可能是无情的和致命的。 克鲁兹毛滴虫和微小毛滴虫都表达一种含唾液酸酶(SA)的蛋白质 活动。克鲁兹毛滴虫有能力将唾液酸转移到 半乳糖受体因此是一种反式唾液酸酶(TS)。一大堆 有证据表明TS是克氏锥虫宿主的重要介体 相互作用，因为它促进锥虫与哺乳动物细胞的附着 并在体内有效地增强了毒力。隐孢子虫也表达了 SA有两个侵染期，即子孢子和裂殖子。隐孢子虫 SA在免疫学上与克氏锥虫酶有关，它可能发挥作用 在腹泻的发生中的作用。 该项目汇集了各个领域的世界顶尖专家。 共同的目标是提高对结构和 克鲁兹毛滴虫和隐孢子虫唾液酸酶的功能。研究：关于 哺乳动物的TS生物学将由校长进行 波士顿新英格兰医学中心的调查员，也就是 霍诺林·沃德博士将对隐孢子虫进行分子表征 酶，这是最近在她的实验室发现的。生物学 约翰·埃德曼博士将对克氏锥虫的昆虫媒介进行研究。 在马萨诸塞大学阿默斯特分校。立体结构 动力学分析将由巴斯的加里·泰勒博士进行 英国，大学。和唾液酸酶抑制剂的合成 分子建模和结构分析将在莫纳什大学进行 澳大利亚大学，马克·冯·伊茨斯坦博士，他为了 该项目已经合成了具有活性的唾液酸衍生物 对阵TS。这些抑制剂的生物学特性将在#年进行检测。 波士顿。 由三位国际知名人物组成的科学咨询委员会 结构、生物学和分子生物学方面的权威人士 碳水化合物和唾液酸结合蛋白(Don Wiley，Stephen博士 Beverly和Roland Schauer)将为首席调查员和 监督拟议研究的进展情况。委员会和 调查人员将每年在波士顿会面一次。 因此，计划项目应该提供对结构的洞察 以及由寄生虫表达的唾液酸酶的生物学 人类的重要疾病。它还可能产生一种化疗药物 治疗这些疾病的药物，因为类似的研究导致了这一发现 流感病毒唾液酸酶抑制剂(由Itzstein博士撰写)，目前 在世界许多地区的临床试验中，包括美国 各州。