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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）：阻断天花（天花的病原体）感染的新型安全疗法对于快速应对生物恐怖主义至关重要。治疗药物可以防止天花传播时，疫苗交付延误，并保护个人的条件，疫苗是禁忌。聚合酶-持续合成能力复合物是理想的治疗靶标，因为它们具有选择特异性（持续合成能力）和广谱（聚合酶）抑制剂的潜力。持续合成因子将DMA聚合酶拴在DMA上，使酶能够合成长链。我们现在已经确定，牛痘病毒（W）的进行性DNA合成需要三种蛋白质，E9 DNA聚合酶和A20，D4 R的持续合成因子。由于这三种牛痘蛋白与天花病毒的相应蛋白至少97%同源，因此预测W治疗剂在天花中靶向相同的功能。我们最近使用我们的快速平板分析法完成了对小型化学品库中52，000种化合物的高通量筛选（HTS）。我们鉴定了21种有效阻断牛痘病毒DNA合成并以可忽略的细胞毒性预防感染的LEAD抑制剂。第二个HTS将添加额外的电极导线。我们的目标是使用体外选择性测定，采用SPR技术和分析治疗抗性病毒，确定每个LEAD抑制剂靶向的三联体（E9/A20/D4）蛋白质。将通过计算机模拟复合采矿获得其他新的类似物。药物化学选择铅化合物将产生抑制剂的上级抗病毒效力和安全性。令人兴奋的是，我们还将采用基于晶体D4-A20缔合的合理药物设计来鉴定高度特异性的痘病毒抑制剂。铅化合物将在CDC进行天花病毒抑制试验。我们将评估LEAD化合物保护小鼠免受痘病毒攻击的功效。我们还将继续确定广谱抑制剂，以防止其他医学上重要的病毒感染。我们的研究旨在产生优秀的治疗方法，在未来，可以采取的药代动力学阶段的测试。我们的希望是开发出一种独特的抑制剂，可以预防痘和其他病毒性疾病。相关性（参见说明）：这些研究的目的是发现治疗方法，将防止天花的传播，如果它成为一种生物恐怖武器。某些治疗药物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，并阻断其他重要的生物恐怖主义因子。