STRUCTURE/FUNCTION OF PROTOZOAN SIALIDASES

克氏锥虫是南美锥虫病的病原体， 使人衰弱的不治之症折磨着拉丁美洲数百万人 美国参考 隐孢子虫引起胃肠道疾病， 免疫功能正常和免疫缺陷的人，特别是那些 艾滋病，感染可能是无情的和致命的。 T. cruzi和C. parvum表达具有唾液酸酶（SA）的蛋白质 活动 t. cruzi SA能够将唾液酸转移到 半乳糖受体，因此是转唾液酸酶（TS）。 大量的 证据表明TS是T.克鲁兹寄主 相互作用，因为它促进锥虫附着到哺乳动物细胞 并有效地增强体内毒力。 隐孢子虫还表达 SA分孢子和裂殖子两个感染阶段。 隐孢子 SA与T. cruzi酶和它可能发挥 在腹泻发生中的作用。 该项目汇集了世界各领域的顶级专家 共同的目标是提高对结构的理解， 对T. cruzi和隐孢子虫。 研究 哺乳动物中TS的生物学将由校长 波士顿新英格兰医学中心的研究者， 博士霍诺琳·沃德将从分子水平上描述 这种酶是她实验室里最近发现的。 生物 对T. cruzi将由约翰·埃德曼博士 在阿默斯特的马萨诸塞州大学。 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 以及基于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 马克·冯·伊茨斯坦博士，为了 这个项目，已经合成了唾液酸衍生物， 针对TS。 抑制剂的生物学特性将在 波士顿 由三位国际知名人士组成的科学咨询委员会 结构，生物学和分子生物学的权威， 碳水化合物和唾液酸结合蛋白（Don Wiley，Stephen 贝弗利和罗兰绍尔）将为主要研究者提供咨询， 监测拟议研究的进展。 委员会和 调查人员将每年在波士顿举行一次会议。 因此，计划项目应提供对结构的深入了解 以及由寄生虫表达的唾液酸酶的生物学， 人类的重大疾病。 它也可能产生一种化疗药物 类似的研究发现， 流感病毒唾液酸酶抑制剂（由Itzstein博士），目前 在世界许多地方的临床试验中，包括美国， states.

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.