Broad spectrum therapeutics targeting resolvase enzymes

项目总结（范围变更）修改后的项目总结（范围变更）U 01 A1082015-O 1“靶向广谱治疗药物UO 1 AI 082015 -01“靶向广谱治疗药物Resolvase酶” 对于生物防御中的应用，期望小分子抑制剂用于生物防御，靶向多种A-C类试剂，因为即使开发一种小分子抑制剂也是困难和昂贵的。我们建议开发分子抑制剂。我们提出了Holliday连接解离酶，这是发现在几个类别A-C初步研究集中在解离酶剂。最初的研究集中在痘病毒中发现的解离酶。这些酶催化所需的复制步骤，其中病毒基因组DNA的多联体被切割成单位长度的基因组用于包装。切割成单位长度的基因组用于包装。酶也是重要的病原性真菌，如球孢子菌，致病球孢子菌，发热，其中代理的山谷热，在那里它是参与线粒体DNA复制。参与线粒体DNA复制。在之前的工作中，我们开发了高通量测定并筛选了> 133，000个我们迄今为止最好的化合物具有抑制活性的IC 50小分子。迄今为止，我们最好的化合物对纯化的解离酶的1C 50为~ 100 nM，对病毒的1C 50为3 uM。我们有~ 100 nM，针对病毒的IC 50为3 μ M。根据审查员的意见修订了我们的目标，并在预计的两年（而不是五年）供资期间取得最大进展。我们预计两年（而不是五年）的资金。将强调新的化合物鉴定，迭代化合物合成，和越来越严格的检测，以开发在动物模型中有活性的痘病毒解离酶抑制剂。体内抗痘病毒活性的抑制剂也将是模型。在致病真菌中测试了抗痘病毒的抑制剂，以努力开发“双重用途”药物疗法。该项目的资金将为5人以上创造就业机会（所有参与群体的全职员工总数为5.45人）。将从美国采购两件设备（荧光板读数器和-80 ° C冷冻机）。实现ARRA的目标。#21453;，从而实现了《反腐败法》的目标。

Project Summary (Change of Scope) Modified Project Summary (Change of Scope) U01 A1082015-O1 "Broad Spectrum Therapeutics Targeting UO1 AI082015-01 "Broad Spectrum Therapeutics Targeting Resolvase Enzymes" For applications in biodefense, it is desirable for small molecule inhibitors to biodefense, target multiple category A-C agents because it is difficult and expensive to develop even one small molecule inhibitor. We propose to develop inhibitors of molecule inhibitor. We propose Holliday junction resolvase enzymes, which are found in several category A-C Initial studies focused on resolvase enzymes agents. Initial studies focused on resolvase enzymes found in poxviruses. These enzymes catalyze a required replication step in which concatemers of the viral genomic DNA are cleaved into unit length genomes for packaging. The cleaved into unit length genomes for packaging. enzyme is also important in pathogenic fungi such as Coccidioldes, the causative Coccidioides, Fever, where agent of Valley Fever, where it is involved in mitochondrial DNA replication. In involved in mitochondrial DNA replication. previous work we developed a high throughput assay and screened >133,000 Our best compound so far has an IC50 small molecules for inhibitory activity. Our best compound so far has an 1C50 against purified resolvase of -100 nM, 1C50 against virus of 3 uM. We have -100 nM, IC50 against virus of 3 uM. revised our Aims in accordance with the reviewers comments, and to maximize our progress over the projected two years (instead of five years) of funding. We projected two years (instead of five years) of funding. will emphasize new compound identification, iterative compound synthesis, and increasingly stringent assays to develop inhibitors of poxvirus resolvases that are active in animal models. Inhibitors active against poxviruses in vivo will also be models. Inhibitors active against poxviruses tested in pathogenic fungi in an effort to develop "dual use" pharmacotherapy. pathogelllic Funding of the project will generate jobs for more than five people (5.45 FTEs summed over all the participating groups). and two pieces of equipment will be purchased (a fluorescence plate reader and a -80¿C freezer) from American sources. advancing the goals of the ARRA. sources, thereby advancing the goals of the ARRA.