Therapeutics that target processivity complex proteins of pox and other viruses

针对痘和其他病毒的持续复合蛋白的治疗

基本信息

批准号：
8466275
负责人：
ROBERT Paul RICCIARDI
金额：
$ 91.72万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2015-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Novel and safe therapeutics that block infection by variola, the causative agent of smallpox, are essential for a rapid response to bioterrorism. Therapeutics can prevent smallpox spread when vaccine delivery is delayed and protect individuals with conditions for whom the vaccine is contraindicated. Polymerase- Processivity complexes are ideal therapeutic targets in that they have the potential to select for both Specific (processivity) and Broad-Spectrum (polymerase) inhibitors. Processivity factors tether DMA polymerase to DMA, enabling the enzyme to synthesize long strands. We have now established that processive DMA synthesis of vaccinia virus (W) requires three proteins, an E9 DMA polymerase and the A20, D4R processivity factors. Because these three vaccinia proteins are at least 97% homologous to the corresponding proteins of variola virus, W therapeutics are predicted to target the same function in variola. We recently completed High Throughput Screen (HTS) of 52,000 compounds from small chemical libraries using our Rapid Plate Assay. We identified 21 LEAD inhibitors that effectively block vaccinia virus DNA synthesis and prevent infection with negligible cell cytotoxicity. A second HTS will add additional LEADS. Our goals are to define which protein of the triad (E9/A20/D4) is targeted by each LEAD inhibitor using an in vitro selectivity assay, employing SPR technology and analyzing therapeutic resistant viruses. Additional new analogs will be obtained by in silico Compound Mining. Medicinal Chemistry of select LEAD compounds will generate inhibitors of superior anti-viral potency and safety. Excitingly, we will also employ Rational Drug Design based on the crystal D4-A20 association to identify highly specific inhibitors of poxviruses. LEAD compounds will be tested for inhibition of variola virus at the CDC. We will evaluate the efficacy of LEAD compounds to protect mice against challenge by poxviruses. We will also continue to define Broad-Spectrum inhibitors that prevent infection of other medically important viruses. Our studies are intended to produce excellent therapeutics that can, in the future, be taken to the pharmokinetic stages of testing. Our hope is to develop a unique class of inhibitors that protect against pox and other viral diseases. RELEVANCE (See instructions): These studies are aimed at discovering therapeutics that will prevent the spread of smallpox, if it becomes used as a bio-terror weapon. The Broad-Spectrum action of certain of these therapeutics will hopefully generate new anti-virals that can be used to prevent current infections that are of medical significance as well as block other important agents of bioterrorism.

描述（由申请人提供）：阻止天花病原体天花感染的新颖且安全的疗法对于快速应对生物恐怖主义至关重要。当疫苗接种延迟时，治疗可以防止天花传播，并保护患有疫苗禁忌症的个体。聚合酶-持续合成复合物是理想的治疗靶点，因为它们有可能选择特异性（持续合成）和广谱（聚合酶）抑制剂。持续加工因子将 DMA 聚合酶束缚在 DMA 上，使酶能够合成长链。我们现在已经确定痘苗病毒 (W) 的持续 DMA 合成需要三种蛋白质、E9 DMA 聚合酶和 A20、D4R 持续因子。由于这三种牛痘蛋白与天花病毒的相应蛋白至少有 97% 同源性，因此 W 疗法预计将针对天花病毒的相同功能。我们最近使用快速板分析完成了对小型化学库中 52,000 种化合物的高通量筛选 (HTS)。我们鉴定出 21 种 LEAD 抑制剂，可有效阻断痘苗病毒 DNA 合成并预防感染，且细胞毒性可忽略不计。第二个 HTS 将添加额外的引线。我们的目标是使用体外选择性测定、采用 SPR 技术并分析治疗耐药病毒来确定每种 LEAD 抑制剂针对三联体 (E9/A20/D4) 中的哪种蛋白质。其他新的类似物将通过计算机复合采矿获得。精选 LEAD 化合物的药物化学将产生具有卓越抗病毒效力和安全性的抑制剂。令人兴奋的是，我们还将采用基于晶体 D4-A20 关联的合理药物设计来识别高度特异性的痘病毒抑制剂。 CDC 将测试 LEAD 化合物对天花病毒的抑制作用。我们将评估 LEAD 化合物保护小鼠免受痘病毒攻击的功效。我们还将继续定义预防其他医学上重要病毒感染的广谱抑制剂。我们的研究旨在产生优秀的治疗方法，这些治疗方法可以在未来进入药代动力学测试阶段。我们希望开发出一类独特的抑制剂来预防痘和其他病毒性疾病。相关性（参见说明）：这些研究旨在发现能够防止天花传播（如果天花被用作生物恐怖武器）的治疗方法。其中某些疗法的广谱作用有望产生新的抗病毒药物，可用于预防具有医学意义的当前感染，并阻止其他重要的生物恐怖主义分子。