EXPLOITATION OF NOVEL DRUG TARGET IN PROTOZOAL INFECTION

原虫感染新药靶点的开发

• 批准号: 2672504
• 负责人: DAVID G RUSSELL
• 金额: $ 53.79万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672504
• 关键词: antiprotozoal agents; drug design /synthesis /production; drug screening /evaluation; microorganism disease chemotherapy; protozoal infection

The infections caused by parasitic protozoa place a severe burden of illness in the World's population. Many of these infections, although not directly fatal, induce extreme morbidity in infected individuals. Current regimens for the treatment of the majority of these diseases are dogged by recurring problems of drug toxicity and side effects, and widespread development of drug-resistance with a restricted spectrum of active compounds. These problems can only intensify therefore it is vital that new targets and novel compounds be developed into antiparasite drugs as soon as possible. This current Program application entitled "Exploitation of Novel Drug Targets in Protozoal Infections" proposes to address these specific problems for malaria, leishmaniasis and amebiasis. The projects show a high degree of unity based on mutually complementary skills, shared goals, and a preexisting interaction between the 4 individual laboratories. All projects propose to target enzymes that have already been identified and show activities that are specific to the parasite. Project 1 has two complementary aims; The exploitation of macrophage-restricted receptors to target active compounds to the endocytic network of Leishmania-infected macrophages, and the development of substrates specific to the parasite's cysteine proteinases as inhibitors of enzyme activity. These activities are required for the growth of axenic amastigotes in culture. Project 2 exploits the requirement for the aspartic hemoglobinase in the degradation of host erythrocyte hemoglobin by the parasite Plasmodium falciparum. To develop a new antimalarials, this project proposes to improve on peptidomimetic inhibitors that have been shown to block parasite growth in culture. Project 3 is aimed analyzing the interactions between the Entameba histolytica cysteine proteinases, which are fundamental to the pathology of invasive amebiasis, with laminin. The investigators propose to identify the region(s) of laminin involved in the tight binding with amebal proteinases to facilitate development of Entameba-specific proteinase inhibitors. Project 4 targets a vital bifunctional alcohol dehydrogenase/acetyl coA reductase, unique to Entameba histolytica, as a novel site a drug action. Sequence analysis of the enzyme reveals homology only with anaerobic prokaryote enzymes suggesting that the alcohol dehydrogenase/acetyl coA reductase will be a specific target. Together these projects combine to exploit the common interest of the Project Leaders and make most efficient use of their broad experience in the diverse disciplines required for effective drug development.

由寄生原生动物引起的感染造成了严重的负担， 世界人口的疾病。 许多感染，虽然不是 直接致命，在受感染个体中引起极端的发病率。 电流 治疗这些疾病中的大多数的方案受到以下因素的困扰： 药物毒性和副作用的问题反复出现， 产生耐药性，活性谱有限 化合物. 这些问题只会加剧，因此至关重要的是， 新的靶标和新的化合物被开发成抗寄生虫药物， 尽快。 这份名为“新药开发”的项目申请 原生动物感染的目标”建议解决这些具体问题， 疟疾、利什曼病和阿米巴病的问题。 这些项目显示， 基于互补技能、共同目标、 以及4个独立实验室之间预先存在的互动。 所有 这些项目建议针对已经确定的酶， 显示出寄生虫特有的活动。 项目1有两个 互补的目的;利用巨噬细胞限制性受体， 将活性化合物靶向利什曼原虫感染的内吞网络， 巨噬细胞，以及寄生虫特异性底物的发展 作为酶活性抑制剂的半胱氨酸蛋白酶。 这些活动 是培养无鞭毛体生长所必需的。 计划2 利用天冬氨酸血红蛋白酶在降解中的需要， 宿主红细胞血红蛋白的含量。 到 开发一种新的抗疟药，该项目建议改善 已被证明可以阻止寄生虫生长的拟肽抑制剂 文化 项目3旨在分析 溶组织内阿米巴半胱氨酸蛋白酶，这是基本的 侵袭性阿米巴病的病理学，与层粘连蛋白。 研究人员建议， 为了鉴定参与紧密结合的层粘连蛋白的区域， 阿米巴蛋白酶促进内阿米巴特异性 蛋白酶抑制剂 项目4的目标是一种重要的双功能酒精 脱氢酶/乙酰辅酶A还原酶，是溶组织内阿米巴特有的， 药物作用的新部位。 酶的序列分析揭示了同源性 只有厌氧原核生物的酶表明酒精 脱氢酶/乙酰辅酶A还原酶将是特异性靶标。 这些项目联合收割机一起利用了 项目负责人，并最有效地利用他们在以下方面的广泛经验： 有效药物开发所需的各种学科。

项目成果

Parasitophorous vacuoles of Leishmania mexicana acquire macromolecules from the host cell cytosol via two independent routes.

墨西哥利什曼原虫的寄生液泡通过两条独立的途径从宿主细胞胞浆中获取大分子。

• DOI: 10.1242/jcs.112.5.681
• 发表时间: 1999
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Schaible,UE;Schlesinger,PH;Steinberg,TH;Mangel,WF;Kobayashi,T;Russell,DG
• 通讯作者: Russell,DG

Structural analysis of plasmepsin II. A comparison with human aspartic proteases.

血浆蛋白酶 II 的结构分析。

• 发表时间: 1998
• 期刊: Advances in experimental medicine and biology
• 作者: Silva,AM;Lee,AY;Erickson,JW;Goldberg,DE
• 通讯作者: Goldberg,DE

Kinetic analysis of plasmepsins I and II aspartic proteases of the Plasmodium falciparum digestive vacuole.

恶性疟原虫消化液泡的血浆蛋白酶 I 和 II 天冬氨酸蛋白酶的动力学分析。

• DOI: 10.1016/0166-6851(96)02651-5
• 发表时间: 1996
• 期刊: Molecular and biochemical parasitology
• 影响因子: 1.5
• 作者: Luker,KE;Francis,SE;Gluzman,IY;Goldberg,DE
• 通讯作者: Goldberg,DE

Naturally-occurring and recombinant forms of the aspartic proteinases plasmepsins I and II from the human malaria parasite Plasmodium falciparum.

来自人类疟疾寄生虫恶性疟原虫的天冬氨酸蛋白酶 I 和 II 的天然存在和重组形式。

• DOI: 10.1016/s0014-5793(99)00805-4
• 发表时间: 1999
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Tyas,L;Gluzman,I;Moon,RP;Rupp,K;Westling,J;Ridley,RG;Kay,J;Goldberg,DE;Berry,C
• 通讯作者: Berry,C

A novel protein targeting domain directs proteins to the anterior cytoplasmic face of the flagellar pocket in African trypanosomes.

一种新型蛋白质靶向结构域将蛋白质引导至非洲锥虫鞭毛袋的前细胞质面。

• DOI: 10.1242/jcs.112.18.3091
• 发表时间: 1999
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Hill,KL;Hutchings,NR;Russell,DG;Donelson,JE
• 通讯作者: Donelson,JE