Expanding the design space of protein-small molecule conjugates

扩大蛋白质-小分子缀合物的设计空间

• 批准号: 10729980
• 负责人: Sarah J. Moore
• 金额: $ 39.88万
• 依托单位: SMITH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729980
• 关键词: Alkynes; Amino Acids; Antibody-drug conjugates; Azides; Binding; Biological; Biotechnology; Caring; Cell model; Cells; Chemicals; Chemistry; Clinical; Combined Modality Therapy; Complex; Coupled; Cysteine; Data; Diagnosis; Directed Molecular Evolution; Disease; Drug Delivery Systems; Drug Targeting; Drug Transport; Engineering; Future; Goals; Hematologic Neoplasms; Immune System Diseases; In Vitro; Kinetics; Libraries; Location; Malignant Neoplasms; Measures; Medical; Medicine; Methods; Minority; Modeling; Molecular; Molecular Target; Oncology; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Physiological; Polymers; Production; Property; Protein Biosynthesis; Proteins; Radial; Reaction; Reporting; Research; Scaffolding Protein; Site; Solid Neoplasm; Structure; Sulfhydryl Compounds; System; Therapeutic; Tissues; Translating; Variant; Work; cancer therapy; clinical care; design; experimental study; fluorophore; improved outcome; in vivo; molecular recognition; nervous system disorder; novel; polypeptide; precision medicine; scaffold; side effect; small molecule; success; targeted treatment; trafficking

PROJECT SUMMARY/ABSTRACT Targeted therapy and targeted drug delivery have revolutionized clinical care of complex disease whenever these options are available – and, yet, only a minority of patients have access to these precision medicine approaches where their care is based on the molecular basis of their disease. Such molecular targeting leads to better patient outcomes and fewer toxic side effects compared to traditional treatment approaches, for a range of diseases. As part of expanding precision medicine to all patients with complex diseases, there is a critical need to meet the molecular targeting gaps in clinical care where such options currently do not exist. Protein- drug conjugates have immense promise in targeted therapy and drug delivery applications, with a number of recent successes in the form of antibody-drug conjugates (ADCs) for cancer therapy. However, numerous design challenges for protein-drug conjugates remain, including narrow therapeutic windows and difficulty in translating success in oncology to other clinical indications. Even within oncology, solid tumors remain significantly more difficult to treat than hematological cancers. Our hypothesis is that the current set of modular components in the design space is limiting and leads to many of the current challenges. Therefore, there is an unmet need to create and validate protein-drug conjugate components and combinations beyond those currently being used. The overall goal of this proposed research is to expand the design space for protein-drug conjugates, enabling this class of molecules to have further success in a wider range of applications in biotechnology and medicine. We propose to validate scaffold proteins and side-chain reactive polymers as modular components for novel protein-drug conjugate structures. As a model protein scaffold for this work, we will use the Fn3 polypeptide fold, which has been demonstrated to be extremely versatile for engineering molecular recognition using rational and directed evolution approaches. We propose to modify model Fn3 proteins with canonical and non-canonical amino acids to enable site-specific bioconjugation reactions (Aim 1). As a novel linker system for protein-drug conjugates, we propose to use side-chain reactive poly(PFPA), as a model polymer for synthesizing protein- polymer-drug conjugates. Side-chain reactive polymers are more chemically versatile than current linkers in use for ADCs, and can serve multiple functions to overcome current ADC limitations. We will functionalize polymer poly(PFPA) to enable conjugation to specific protein sites, and load releasable small molecules onto the polymer, using a range of drug loading ratios, with combinations of small molecules to enable combination therapy (Aim 2). We will measure and model cellular and tissue trafficking of the conjugates (Aim 3), a key consideration for therapeutic success. The overall objective of this application is to extend the capacity of scaffold proteins and side-chain reactive polymers to fill the gap in molecular targeting challenges. Our work will have a broader positive impact by establishing methods for synthesizing bioconjugates using a myriad of polypeptide folds and polymer linkers, towards the ultimate goal of creating targeted treatments for every patient who needs them.

项目总结/摘要 靶向治疗和靶向药物递送已经彻底改变了复杂疾病的临床护理， 这些选择是可行的，但只有少数患者能够获得这些精准医疗。 他们的治疗是基于他们疾病的分子基础的方法。这种分子靶向引导 与传统治疗方法相比，在一定范围内， 疾病。作为将精准医疗扩展到所有复杂疾病患者的一部分， 需要满足临床护理中的分子靶向差距，目前不存在这种选择。蛋白质- 药物缀合物在靶向治疗和药物递送应用中具有巨大的前景， 抗体-药物缀合物（ADC）形式用于癌症治疗的最新成功。许多设计 蛋白质-药物缀合物的挑战仍然存在，包括狭窄的治疗窗口和翻译困难， 在肿瘤学和其他临床适应症方面取得成功。即使在肿瘤学中，实体瘤仍然明显更多 比血液癌症更难治疗我们的假设是， 设计空间是有限的，并导致许多当前的挑战。因此，有一个未满足的需要， 并验证目前使用的蛋白质-药物偶联物组分和组合以外的组分和组合。的 这项拟议研究的总体目标是扩大蛋白质-药物缀合物的设计空间， 这类分子在生物技术和医学的更广泛应用中取得了进一步的成功。我们 建议验证支架蛋白和侧链反应性聚合物作为新的 蛋白质-药物缀合物结构。作为这项工作的模型蛋白支架，我们将使用Fn 3多肽 折叠，这已被证明是非常通用的工程分子识别使用合理的 和定向进化方法。我们建议用经典和非经典的修饰模型Fn 3蛋白， 氨基酸以实现位点特异性生物缀合反应（目的1）。作为一种新型的蛋白质-药物连接系统， 结合物，我们建议使用侧链反应性聚（PFPA），作为合成蛋白质的模型聚合物， 聚合物-药物缀合物。侧链反应性聚合物比目前使用的连接剂在化学上更通用 可提供多种功能，以克服当前ADC的局限性。我们将功能化聚合物 聚（PFPA），使共轭特定的蛋白质位点，并加载可释放的小分子到聚合物上， 使用一系列的药物负载比，与小分子的组合以实现组合治疗（Aim 2）。我们将测量和模拟缀合物的细胞和组织运输（目标3），这是 治疗成功。本申请的总体目标是扩展支架蛋白的能力， 侧链反应性聚合物来填补分子靶向挑战中的差距。我们的工作将有更广泛的 通过建立使用无数多肽折叠合成生物缀合物的方法， 聚合物连接器，朝着为每一个需要它们的患者创造靶向治疗的最终目标。