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）：天花的致病药物瓦里奥拉（Variola）阻止感染的新颖和安全疗法对于快速对生物恐怖主义的快速反应至关重要。当疫苗输送延迟时，治疗剂可以防止天花扩散，并保护疫苗禁忌的条件的人。聚合酶 - 加工性复合物是理想的治疗靶标，因为它们有可能选择特定（加工性）和广谱（聚合酶）抑制剂。加工性因素将DMA聚合酶绑定到DMA，从而使酶合成长链。现在，我们已经确定谷谷病毒（W）的过程DMA合成需要三种蛋白质，一个E9 DMA聚合酶和A20，D4R杂化因子。由于这三种离子蛋白至少与Variola病毒的相应蛋白质同源97％，因此预计W疗法可以靶向Variola中相同的功能。最近，我们使用快速板测定法完成了从小型化学文库中的52,000种化合物的高吞吐量屏幕（HTS）。我们确定了21种铅抑制剂，可有效阻断疫苗病毒DNA合成并防止可忽略不计的细胞毒性感染。第二个HTS将增加其他潜在客户。我们的目标是使用体外选择性测定法，采用SPR技术并分析治疗性耐药性病毒，定义每个铅抑制剂的三合会（E9/A20/D4）的哪种蛋白质（E9/A20/D4）。在硅化合物挖掘中将获得其他新类似物。精选铅化合物的药物化学将产生优质抗病毒效力和安全性的抑制剂。令人兴奋的是，我们还将基于Crystal D4-A20关联采用合理的药物设计来识别高度特异性的痘病毒抑制剂。将测试铅化合物在CDC处抑制Variola病毒。我们将评估铅化合物的功效，以保护小鼠免受痘病毒的挑战。我们还将继续定义宽光谱抑制剂，以防止感染其他重要的医学病毒。我们的研究旨在产生出色的治疗剂，将来可以将其带入测试的药物动力学阶段。我们的希望是开发一种独特的抑制剂，以防止痘痘和其他病毒疾病。相关性（请参阅说明）：这些研究旨在发现如果将其用作生物恐怖武器，则可以防止天花传播。某些这些治疗剂的广泛作用将有望产生新的抗病毒，可用于防止目前具有医学意义的感染以及阻止生物恐怖主义的其他重要药物。