Broad spectrum therapeutics targeting resolvase enzymes

针对分解酶的广谱疗法

• 批准号: 7643670
• 负责人: Frederic D Bushman
• 金额: $ 101.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643670
• 关键词: Address; Affect; Aflatoxins; Agreement; Air; American; Americas; Anatomy; Animal Model; Animals; Antibiotics; Antigens; Applications Grants; Aspergillus; Authorization documentation; Award; Back; Bar Codes; Biocontrols; Biological Assay; Bioterrorism; Blast Cell; Boxing; Budgets; CD2 gene; CD8-Positive T-Lymphocytes; Calendar; Calibration; California; Cataloging; Catalogs; Categories; Cell Culture Techniques; Cell Therapy; Cells; Certification; Chemicals; Chest; Chronic Obstructive Airway Disease; Cleaved cell; Clinical; Coccidioides; Coccidioidomycosis; Code; Collaborations; Communities; Complement; Complementary DNA; Confidential Information; Consultations; Contracts; Crohn' s disease; Cruciform DNA; Custom; DNA; DNA Integration; DNA Vaccines; DNA biosynthesis; Databases; Development; Diagnostic; Diagnostic tests; Diet; Dimensions; Direct Costs; Disclosure; Disease; Drug Formulations; Drug resistance; Dyes; Emerging Communicable Diseases; Engineering; Enzyme Tests; Enzymes; Equipment; Event; Excision; Excretory function; Face; Failure; Fever; Fluorescence; Foundations; Funding; Gene Deletion; Gene Expression; Gene Transfer; Gene-Modified; Genes; Genetic; Genome; Genomics; Genotype; Goals; Government; Grant; Growth; HIV; HIV Infections; Health; Healthcare; Histologic; Holliday Junction Resolvases; Home environment; Human; Human Genome; IACUC; Image; Immune; Immune response; Immunotherapy; In Vitro; Income; Individual; Induced Hyperthermia; Infection; Inhibitory Concentration 50; Institution; Instruction; Laboratories; Laboratory Animals; Laboratory Research; Lead; Legal; Length; Libraries; Liquid substance; Lung; Lung diseases; Magnaporthe; Mails; Mali; Manuals; Mediation; Medical; Metabolism; Methods; Microbiology; Minor; Mitochondrial DNA; Modeling; Monitor; Mus; Mutagenesis; Names; Naphthyridines; Occupations; Paint; Paper; Partner in relationship; Pathogenesis; Pattern; Pennsylvania; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Pisum sativum; Pneumonia; Policies; Powder dose form; Poxviridae; Price; Principal Investigator; Privacy; Process; Property; Proteins; Protocols documentation; Public Health; Published Comment; Publishing; Reader; Refrigeration; Reporting; Research; Research Personnel; Resistance; Resolution; Resolvase; Resources; Respiratory System; Respiratory tract structure; Rice; Rights; Risk; Rodent Model; Role; Running; Safety; Sampling; Science; Screening procedure; Secure; Security; Services; Shipping; Ships; Site; Smallpox; Smallpox Vaccine; Source; Staging; Stainless Steel; Steel; Stem cells; Sum; System; Telefacsimile; Telephone; Temperature; Testing; Text; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Thick; Time; Toxicology; Trademark; U-Series Cooperative Agreements; United States; United States National Institutes of Health; Universities; Vaccine Antigen; Vaccines; Vaccinia; Vaccinia virus; Vaccinia virus complement-control protein; Validation; Viral; Virulence; Virus; Virus Diseases; Wages; Weight; Work; Yeasts; absorption; abstracting; base; biodefense; biosignature; contactin; cost; density; design; digital; efficacy testing; fungus; gene therapy; high throughput screening; improved; in vivo; inhibitor/antagonist; interest; meetings; microbiome; mouse model; mutant; nikkomycin; pathogen; peer; pressure; prevent; proctolin; programs; protein-histidine kinase; public health relevance; resistant strain; respiratory; response; scaffold; seal; small molecule; solid state; styrofoam; therapeutic gene; therapeutic target; tool; transglutaminase 2; voltage

text here that is the new abstract information for your application. This section must be no Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. 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. -(} -�O D)� ... 10 11:20AM (GMT-04:00) 11 :20AM (GMT-014:OO) 06/19/2009 too r=` Ofd :mN 0)_ d-0 =ii =d0 a-Ec w-w goo 06/19/2009 10:31 FAX 06/19/2009 215 9557 215 898 9557 UPENN MICROBIOLOGY t012/025 IiZl 012/025

此处的文本是您的应用程序的新摘要信息。此部分必须是 no 在此处输入作为您的申请的新摘要信息的文本。此部分的文本长度不得超过 30 行。 项目摘要（范围变更） 修改后的项目摘要（范围变更） U01 A1082015-O1 “针对 UO1 的广谱疗法 AI082015-01 “针对解离酶的广谱疗法” 对于生物防御应用，需要小分子抑制剂进行生物防御，靶向多种 A-C 类药物，因为即使开发一种小分子抑制剂也是困难且昂贵的。我们建议开发分子抑制剂的抑制剂。我们建议使用霍利迪连接解离酶，该酶在几个主要针对解离酶制剂的 A-C 类初始研究中被发现。最初的研究集中在痘病毒中发现的分解酶。这些酶催化所需的复制步骤，其中病毒基因组 DNA 的串联体被切割成单位长度的基因组以进行包装。被切割成单位长度的基因组用于包装。该酶在病原真菌中也很重要，例如球孢子菌（球孢子菌）、发烧（谷热的病原体），它参与线粒体 DNA 复制。参与线粒体DNA复制。在之前的工作中，我们开发了一种高通量测定法，并筛选了 >133,000 种迄今为止我们最好的化合物，其小分子具有抑制活性的 IC50。迄今为止，我们最好的化合物针对纯化的拆分酶的 1C50 为 -100 nM，针对病毒的 1C50 为 3 uM。我们对病毒的 IC50 为 -100 nM，为 3 uM。根据审稿人的意见修改了我们的目标，并在预计的两年（而不是五年）的资助中最大限度地取得进展。我们预计提供两年（而不是五年）的资金。将强调新的化合物鉴定、迭代化合物合成和日益严格的检测，以开发在动物模型中具有活性的痘病毒分解酶抑制剂。体内对痘病毒具有活性的抑制剂也将成为模型。在病原真菌中测试了针对痘病毒的活性抑制剂，以开发“双重用途”药物疗法。该项目的病理资助将为超过 5 人创造就业机会（所有参与群体的 FTE 总计为 5.45）。将从美国采购两台设备（荧光读板机和-80℃冰箱）。推进 ARRA 的目标。源，从而推进 ARRA 的目标。 -(} -�O D）� ... 10 上午 11:20 (GMT-04:00) 上午 11:20 (GMT-014:OO) 2009年6月19日 也 r=` 奥夫德 :mN 0)_ d-0 =ii =d0 α-Ec w-w 粘性物 2009年6月19日 10:31 传真 2009年6月19日 215 9557 215 898 9557 宾夕法尼亚大学微生物学 t012/025 伊兹尔 012/025