Universal Protein Carrier Scaffold for Small Molecules and Peptide Therapeutics

适用于小分子和肽治疗的通用蛋白质载体支架

• 批准号: 7944177
• 负责人: David Ian Rabuka
• 金额: $ 49.99万
• 依托单位: REDWOOD BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944177
• 关键词: Address; Adverse effects; Aldehydes; Animal Testing; Area; Biological; Biological Assay; Biomedical Technology; Calcitonin; Capital; Carrier Proteins; Cells; Chemicals; Consensus Sequence; Cyclic AMP; Cysteine; Data; Development; Diabetes Mellitus; Disease; Drug Delivery Systems; Drug Industry; Drug Kinetics; Enzymes; Frequencies; Funding; Generations; Genetic; Goals; Grant; Human; In Vitro; Length; Libraries; Medical; Methods; Modification; Molecular Weight; Osteoporosis; Peptides; Pharmaceutical Preparations; Plasmids; Positioning Attribute; Post-Translational Protein Processing; Proteins; Recombinant Proteins; Recombinants; Redwood; Research; Scaffolding Protein; Screening procedure; Serum Albumin; Site; Source; Sulfatases; System; Technology; Therapeutic; Time; Treatment Cost; Vertebral column; Work; Yeasts; base; cost; design; dosage; drug efficacy; effective therapy; fluorophore; formylglycine; glucagon-like peptide 1; improved; in vitro Assay; interest; peptide analog; scaffold; small molecule; therapeutic protein

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-EB-102, Development of biomedical technologies and systems Low molecular weight small molecules and peptides often have limited therapeutic utility because of poor pharmacokinetic profile and rapid clearance. As a result, there has been a large effort focused on the development of drug delivery systems, including using large biomolecules as carrier proteins. Protein carriers offer several substantial advantages over other delivery methods including relatively low off-target activity, resulting in fewer side effects. Many of these carrier proteins are recombinant genetic fusions with a therapeutic peptide of interest. Alternately, chemically elaborating carrier proteins with small molecule drugs or peptides can also render the peptide therapeutic more potent and longer lasting. The optimal benefit of protein chemical modification is achieved when the modification is site-specific. However, none of the existing methods for site-specific protein modification are simple, non-toxic, and applicable to proteins expressed in either mammalian or bacterial cells. As a consequence, peptide therapeutics that could be improved by chemical modification have yet to be optimized in this manner. Redwood Bioscience Inc. has developed a technology platform that allows us to chemically modify proteins in a controlled, site-specific manner. The end result is a protein elaborated at a single point. We believe this technology can be used to generate a carrier protein scaffold for delivery of peptide drugs. This scaffold will be homogenous, easy to chemically elaborate, and result in cost-effective, long-lasting protein conjugate therapies to treat unmet medical needs. If successful, we believe this work will change the utility of protein therapeutics by enabling rapid use of small molecules and peptides that otherwise would not be useful as treatment for disease. Our technology will yield higher quality homogenous protein products, reduced dosage frequency resulting in lower treatment costs, and with higher specific biological activity compared to the free peptide drugs or other conjugation methods currently used in the pharmaceutical industry. The research is to be initially carried out by a team of three chemists and biologists, to be funded through this grant. Successful completion of the aims in this proposal will generate the required scientific data necessary to approach outside private sources of capital. This will allow us to grow the company and further develop our commercial targets and hire additional full time scientific and support staff. Redwood Bioscience's aldehyde-tag technology can be applied to create modified human serum albumin proteins. These proteins will be attached to peptide-based drugs and the resulting conjugates demonstrated to be efficacious, cost-effective therapies for diabetes and osteoporosis.

描述（由申请人提供）：此申请解决广泛的挑战领域（06）启用技术和特定挑战主题，06-EB-102，生物医学技术和系统的开发低分子量小分子和肽通常由于较差的药物动力学概况和快速清除率而经常具有有限的治疗效用。结果，已经进行了巨大的努力，集中在药物输送系统的开发上，包括使用大型生物分子作为载体蛋白。蛋白质载体比其他递送方法（包括相对较低的脱靶活动）提供了几个可观的优势，从而减少了副作用。这些载体蛋白中的许多是具有感兴趣的治疗肽的重组遗传融合。另外，用小分子药物或肽的化学阐述载体蛋白也可以使肽治疗性更有效，更持久。当修饰特定地点时，可以实现蛋白质化学修饰的最佳益处。但是，现有的特异性蛋白质修饰方法都不是简单，无毒的，并且适用于在哺乳动物或细菌细胞中表达的蛋白质。结果，可以通过这种方式对化学修饰进行改进的肽疗法尚待优化。 Redwood Bioscience Inc.开发了一个技术平台，该平台使我们能够以受控的，特定于现场的方式化学修改蛋白质。最终结果是在一个点详细阐述的蛋白质。我们认为，该技术可用于生成载体蛋白支架以递送肽药物。这种脚手架将是同质的，易于化学精细的，并导致具有成本效益的持久蛋白质共轭疗法，以治疗未满足的医疗需求。如果成功的话，我们认为这项工作将通过快速使用小分子和肽来改变蛋白质治疗剂的实用性，否则这些分子和肽作为疾病的治疗方法。我们的技术将产生更高质量的同质蛋白质产品，剂量降低，从而降低治疗成本，并且与当前在制药行业中使用的游离肽药物或其他共轭方法相比，具有更高的特定生物学活性。这项研究最初是由三位化学家和生物学家组成的团队进行的，并通过这笔赠款资助。在该提案中成功完成目标将产生所需的科学数据，以便在私人资本之外接近私人资本来源。这将使我们能够发展公司并进一步发展我们的商业目标，并聘请额外的全职科学和支持人员。 Redwood Bioscience的醛TAG技术可用于创建改良的人血清白蛋白蛋白。这些蛋白质将附着在基于肽的药物上，结果证明是有效，具有成本效益的糖尿病和骨质疏松症的疗法。