Generation of novel HCV drugs through engineereing of the cssA gene

通过改造 CSSA 基因产生新型 HCV 药物

• 批准号: 7595765
• 负责人: Ake P Elhammer
• 金额: $ 30万
• 依托单位: AUREOGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595765
• 关键词: Adverse effects; Alanine; Amino Acid Substitution; Amino Acids; Anabolism; Animal Model; Antifungal Agents; Area; Autoimmune Diseases; Bacteria; Biological Factors; Cessation of life; Characteristics; Chemicals; Clinic; Code; Communicable Diseases; Complex; Cyclic Peptides; Cyclosporine; Cyclosporins; DNA Sequence Rearrangement; Data; Development; Disease; Engineering; Evaluation; Family; Family member; Foxes; Generations; Genes; Genetic; Genetic Engineering; Goals; HIV; Health; Hepatitis C; Hepatitis C virus; Human; Immunosuppressive Agents; In Situ; In Vitro; Individual; Infection; Kidney Failure; Kidney Transplantation; Knock-in Mouse; Knock-out; Knowledge; Logic; Malignant Neoplasms; Marketing; Medial; Mediating; Methodology; Methods; Minor; Modification; Molds; Multi-Drug Resistance; Multienzyme Complexes; Mutagenesis; Organ Transplantation; Organic Chemistry; Organism; Parents; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Positioning Attribute; Preparation; Probability; Procedures; Production; Prokaryotic Cells; Proline; Property; Recruitment Activity; Reporting; Research Design; Ribosomes; Role; Route; Sales; Sarcosine; Side; Specificity; Structure; Structure-Activity Relationship; Synthesis Chemistry; System; Therapeutic; Time; Valine; Virus; Work; abstracting; analog; anti-hepatitis C; base; cancer cell; cost; cost effective; drug candidate; fungus; genetic manipulation; improved; interest; leucine methyl ester; mortality; nephrotoxicity; novel; peptide synthase; research study; tool; transplantation medicine

DESCRIPTION (provided by applicant): HCV infections are a prevalent and growing health problem. It is estimated that as many as 2% of the US population, and 2.5% of the population world-wide, are infected by HCV. The disease currently causes 15,000 deaths/year in US alone, a number that is predicted to increase three-fold by 2010. Treatment options for HCV infected patients are quite limited, and none of the currently available treatments has a better than 50% probability of eliminating the infection from the patient. Consequently, there is a significant, and immediate unmet medial need for new and better drugs for the treatment of HCV infections. The cyclic peptides constitute a class of compounds that have made crucial contributions human health. These compounds have a considerable presence in several therapeutic areas, ranging from infectious diseases, to cancer and even autoimmune disorders. The discovery of the immunomodulatory cyclic peptide Cyclosporin A (CsA) 50 years ago had a truly profound impact and literally ushered in the era of modern transplantation medicine. Although cyclic peptides often are very efficient drugs, they are also complex natural product molecules (isolated from bacteria and fungi) and as such, they are difficult and expensive to synthesize and/or modify with conventional, synthetic chemistry-based methodologies. Consequently, currently used cyclic peptide-based drugs are either native compounds or native compounds with minor modifications. The vast majority of these compounds have not been optimized for human use and, consequently, the full potential of cyclic peptides, as human therapeutics, has not been explored. The overall goal of the project outlined in this proposal is to use a novel genetic engineering approach that allows cost-effective generation and production of both modified and new cyclic peptides, to generate new and improved anti-HCV drug candidates. The established immunomodulatory drug CsA, a compound with a wide range of pharmacological activities that includes anti-HCV activity, will be used as engineering template. The project involves development of methodologies and a set of genetic tools that allows introduction of modifications to the structure of native CsA by engineering the non-ribosomal peptide synthetase (NRPS) complex responsible its synthesis, in the producer organism Tolypocladium inflatum. Successful implementation of the envisioned genetic engineering approach will not only allow preparation of the envisioned novel anti-HCV drug candidate(s), but also compounds for other therapeutic applications, such as antifungal and antiparasitical compounds and perhaps even derivatives that retain the excellent immunomodulatory properties of native CsA, but not the nephrotoxicity. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) constitutes a significant and rapidly growing health problem world-wide. HCV infections are associated with considerable morbitity and mortality and existing therapies allows no more than a 50% probability of eliminating the virus form an infected patient. The principal aim of the proposed project is to use a novel genetic engineering approach to develop new, efficacious and well-tolerated drugs for the treatment of HCV infections.

描述（由申请人提供）：HCV 感染是一个普遍且日益严重的健康问题。据估计，多达 2% 的美国人口和 2.5% 的全球人口感染了 HCV。目前，仅在美国，该疾病每年就会导致 15,000 人死亡，预计到 2010 年，这一数字将增加三倍。HCV 感染患者的治疗选择非常有限，目前可用的治疗方法中没有一种方法的治愈率高于 50%。消除患者的感染。因此，对于用于治疗 HCV 感染的新的和更好的药物存在显着且紧迫的未满足的医疗需求。环肽是一类对人类健康做出重要贡献的化合物。这些化合物在多个治疗领域中占有相当大的份额，从传染病到癌症，甚至自身免疫性疾病。 50年前，免疫调节环肽环孢菌素A（CsA）的发现产生了真正深远的影响，真正开创了现代移植医学时代。尽管环肽通常是非常有效的药物，但它们也是复杂的天然产物分子（从细菌和真菌中分离出来），因此，用传统的基于合成化学的方法合成和/或修饰它们是困难且昂贵的。因此，目前使用的基于环肽的药物要么是天然化合物，要么是经过微小修饰的天然化合物。这些化合物中的绝大多数尚未针对人类使用进行优化，因此，环肽作为人类治疗药物的全部潜力尚未得到探索。该提案中概述的项目的总体目标是使用一种新颖的基因工程方法，可以经济有效地生成和生产修饰的和新的环肽，以产生新的和改进的抗 HCV 候选药物。已建立的免疫调节药物CsA是一种具有广泛药理活性（包括抗HCV活性）的化合物，将用作工程模板。该项目涉及方法学和一套遗传工具的开发，通过在生产生物 Tolypocladium inflatum 中改造负责合成的非核糖体肽合成酶 (NRPS) 复合物，可以对天然 CsA 的结构进行修饰。成功实施设想的基因工程方法不仅可以制备设想的新型抗HCV候选药物，还可以制备用于其他治疗应用的化合物，例如抗真菌和抗寄生虫化合物，甚至可能保留优异的免疫调节特性的衍生物天然 CsA 的影响，但不是肾毒性。公共卫生相关性：丙型肝炎病毒 (HCV) 是全球范围内一个严重且迅速增长的健康问题。 HCV 感染与相当大的发病率和死亡率相关，现有疗法消除感染患者体内病毒的可能性不超过 50%。该项目的主要目的是利用新型基因工程方法开发新的、有效的、耐受性良好的药物来治疗丙型肝炎病毒感染。