Sustainable Synthesis of Enfuvirtide

恩夫韦肽的可持续合成

• 批准号: 8541523
• 负责人: MICHAEL C PIRRUNG
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-26 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541523
• 关键词: Address; Amino Acids; Anti-Retroviral Agents; C-terminal; Chemicals; Chemistry; Clinical; Coupling; Development; Disease; Drug Compounding; Education; Fuzeon; Generations; HIV; HIV drug resistance; HIV-1; Health; Hispanics; Human; Infection; Institution; Ligation; Methods; Molecular Target; Multi-Drug Resistance; N-terminal; Organic Chemistry; Organic Synthesis; Outcome; Patients; Peptide Synthesis; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacopoeias; Pharmacotherapy; Physical condensation; Procedures; Production; Proteins; Public Health; Reagent; Research; S Phase; Salvage Therapy; Serine; Solid; Solutions; Solvents; T-20; Techniques; Therapeutic; Work; base; cost; novel; operation; performance site; polypeptide; programs; public health relevance; wasting

DESCRIPTION (provided by applicant): Our overall research program addresses the need for much more efficient methods of synthesizing and manufacturing peptide- and protein-based drugs. The objective of this application is the development, using novel peptide coupling/ligation chemistries, of two new syntheses of enfuvirtide (below) that are far more sustainable than the extant enfuvirtide synthesis. The aims for this project are: 1. Modify the existing fragment condensation synthesis of enfuvirtide to generate the N-terminal (1- 16) fragment and the C-terminal (27-36) fragment via solution-phase synthesis using recently demonstrated N-carboxyanhydride (NCA) couplings (enhanced by solvophobic techniques) and serine ligation methods. 2. Develop a de novo synthesis of enfuvirtide using sub-segments from Aim 1 assembled by serine ligations to form the serine-rich N-terminal (1-11) and C-terminal (30-36) fragments, followed by serine ligation of these fragments to a central (12-29) fragment. The expected outcomes of this work include: procedures that enable preparative production of the enfuvirtide drug substance in fewer operations with reduced use of reagents and solvents and the generation of significantly less chemical waste; demonstration of novel NCA couplings and serine ligations in the context of a challenging molecular target that will endorse the strategy for application to other peptide therapeutics. Synthesis of enfuvirtide is relevant to human health because it is a valuable and unique antiretroviral drug for the treatment of HIV-1 infection. However, the cost of enfuvirtide therapy (related to its high manufacturing costs) is prohibitive, so it is typically held in reserve for "salvage" therapy in patients with multi-drug resistant HIV. The impact of the work will be based on both the potential to drive down the cost of a valuable drug therapy as well as the provision of guidance to others aiming to develop new methods for peptide drug preparation. This project will utilize the following methods: organic synthesis, peptide synthesis, and solid-phase synthesis.

描述（由申请人提供）：我们的整体研究计划解决了对合成和生产基于肽和蛋白质的药物的更有效方法的需求。 该应用的目的是使用新型肽耦合/连接化学物质的开发，这些肽偶合成的两种新合成（下图）比现存的enfuvirtide合成更为可持续。该项目的目的是：1。修改enfuvirtide的现有片段凝结合成，以生成N末端（1-16）片段（1-16）片段和C末端（27-36）片段（27-36）片段，该片段使用最近证明的N-羧基氢化物（NCA）耦合（通过溶恐惧症技术增强）和丝氨酸连接方法。 2。使用丝氨酸绑扎组装的AIM 1的子细分形成erinine富含丝氨酸的N末端（1-11）和C末端（30-36）片段，然后进行丝氨酸片段，然后进行丝氨酸连接，然后进行丝氨酸连接这些碎片到中央（12-29）片段。这项工作的预期结果包括：能够在减少使用试剂和溶剂的情况下，可以使enfuvirtide药物的制备产生能够制备生产，并产生明显较少的化学废物；在一个充满挑战的分子靶标的背景下，新型NCA耦合和丝氨酸绑扎的证明，该靶标将认可应用于其他肽疗法的策略。 enfuvirtide的合成与人类健康有关，因为它是一种有价值且独特的抗逆转录病毒药物，用于治疗HIV-1感染。但是，Enfuvirtide治疗的成本（与其高生产成本有关）是过于良好的，因此通常将其用于多药抗HIV患者的“挽救”疗法储备。这项工作的影响将基于降低有价值的药物疗法成本的潜力，以及向其他旨在开发肽药物制备方法的新方法的指导。该项目将利用以下方法：有机合成，肽合成和固相合成。