Plasmodium signal peptide peptidase as a novel antimalarial target

我们假设信号肽肽酶（SPP）是病原性原生动物的极好药物靶标， 特别是引起疟疾疟原虫物种。我们已经获得的数据表明，人类的抑制剂， SPP抑制恶性疟原虫SPP（mSPP），并且这些SPP抑制剂不仅能够杀死恶性疟原虫， falciparum和其他原虫，T. gondii和T.布鲁塞。在此，我们建议扩展这些 观察结果提供了促进选择性恶性疟原虫SPP（mSPP）发展的基本原理 抑制剂，并提供开发这些选择性抑制剂所需的工具和基础设施。SPP是一个 膜内切割蛋白酶家族的一员。在人类中，SPP及其同系物切割 II型膜蛋白的跨膜结构域。相反，早老素（PS），这是相关的 在膜内切割中，N-乙酰基蛋白酶切割I型膜蛋白的跨膜结构域。 SPP似乎能够在没有任何蛋白质辅因子的情况下作为蛋白酶起作用，而PS是催化性的。 作为一种多蛋白复合物被称为分泌酶。PS已被广泛研究作为治疗 阿尔茨海默病（AD）的靶点。事实上，几乎每一家大型制药公司都有一个 大量的分泌酶抑制剂（GSI）发现计划，和几个GSI现在在人体试验。特别 一些GSI能够抑制人类SPP和mSPP的活性。 人类和其他脊椎动物表达SPP的多种同源物，而许多原生动物寄生虫，如 P.恶性疟原虫。T. gondii、弓形虫C. parvum、小隐翅虫G. lamblia和E.溶组织菌含有单一SPP基因。敲除或 在秀丽隐杆线虫、果蝇或斑马鱼中敲低单个SPP基因导致胚胎致死 表型。因此，观察到原生动物病原体含有单一成员的SPP蛋白， 家族提供了一个令人信服的理由来假设这些生物体中SPP的抑制将是致命的， 因此是广泛的病原性原生动物的有吸引力的治疗靶标。事实上，这一假设是 这一点得到了我们初步数据的有力支持。验证SPP作为未来抗原虫的可行蛋白 发展与疟疾寄生虫恶性疟原虫的具体重点，我们将利用多方面的方法 利用生物、基因和化学技术。

We hypothesize that signal peptide peptidase (SPP) is a superb drug target for pathogenic protozoans, and in particular Plasmodium species that cause malaria. We have obtained data showing that inhibitors of human SPP inhibit P. falciparum SPP (mSPP) and that these SPP inhibitors are capable of killing not only P. falciparum but also other protozoal parasites, T. gondii and T. brucei. Herein we propose to extend these observations to provide the rationale that will spur development of selective P. falciparum SPP (mSPP) inhibitors and provide the tools and infrastructure needed to develop those selective inhibitors. SPP is one member of a family of intramembrane cleaving, aspartyl proteases. In humans SPP and its homologs cleave the transmembrane domain of type II membrane proteins. In contrast, the presenilins (PSs), which are related intramembrane cleaving, aspartyl proteases cleave the transmembrane domain of type I membrane proteins. SPP appears capable of functioning as a protease with out any protein co-factors, whereas PS is catalytically active as a multi-protein complex known as ¿-secretase. PSs have been intensively studies as therapeutic targets in Alzheimer's disease (AD). Indeed, nearly every major pharmaceutical company has had a substantial ¿-secretase inhibitor (GSI) discovery program, and several GSIs are now in human trials. Notably some GSIs are capable of inhibiting the activity of human SPP and mSPP. Humans and other vertebrates express multiple homologues of SPP, while many protozoan parasites such as P. falciparum. T. gondii, C. parvum, G. lamblia, and E. histolytica contain a single SPP gene. Knockout or knockdown of a single SPP gene in C.elegans, Drosophila or Zebrafish results in an embryonic lethal phenotype. Thus, the observation that the protozoan pathogens contain a single member of the SPP protein family offers a compelling reason to hypothesize that inhibition of SPP in these organisms would be lethal and therefore an attractive therapeutic target for a broad range of pathogenic protozoans. Indeed, this hypothesis is strongly supported by our preliminary data. To validate SPP as a viable protein for future antiprotozoal development with a specific focus on the malarial parasite P. falciparum, we will utilize a multifaceted approach using biological, genetic and chemical techniques.