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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要靶向治疗和靶向药物输送已经彻底改变了复杂疾病的临床护理这些选择是可用的——然而，只有少数患者可以获得这些精准医疗他们的治疗基于其疾病的分子基础。与传统治疗方法相比，可实现更好的患者治疗效果和更少的毒副作用作为将精准医疗扩展到所有患有复杂疾病的患者的一部分，有一个关键的问题。需要满足目前不存在此类选择的临床护理中的分子靶向差距。药物偶联物在靶向治疗和药物输送应用中具有巨大的前景，其中有许多最近以抗体药物偶联物 (ADC) 的形式用于癌症治疗取得了成功。蛋白质-药物缀合物面临的挑战仍然存在，包括治疗窗口狭窄和翻译困难即使在肿瘤学领域，实体瘤的成功率仍然显着高于其他临床适应症。我们的假设是，当前的模块化组件集比血液癌症更难治疗。设计空间是有限的，并导致了当前的许多挑战，因此，创造的需求尚未得到满足。并验证目前使用之外的蛋白质-药物缀合物成分和组合。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，使之成为可能类分子在生物技术和医学领域的更广泛应用中取得进一步的成功。提议验证支架蛋白和侧链反应性聚合物作为新型模块化组件作为这项工作的模型蛋白质支架，我们将使用 Fn3 多肽。折叠，已被证明在使用理性工程分子识别方面具有非常多的用途我们建议用规范和非规范的方法修改模型 Fn3 蛋白。氨基酸以实现位点特异性生物共轭反应（目标 1）作为蛋白质-药物的新型连接系统。缀合物，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-药物缀合物比目前使用的连接剂具有更多的化学用途。用于 ADC，并且可以提供多种功能以克服当前 ADC 的局限性。我们将对聚合物进行功能化。聚（PFPA）能够与特定的蛋白质位点缀合，并将可释放的小分子加载到聚合物上，使用一系列药物负载比，结合小分子以实现联合治疗（目标 2) 我们将测量和模拟缀合物的细胞和组织运输（目标 3），这是考虑的一个关键因素。该应用的总体目标是扩展支架蛋白和的能力。侧链反应性聚合物填补了分子靶向挑战的空白。通过建立使用无数多肽折叠合成生物缀合物的方法来产生积极影响聚合物连接器，以实现为每个需要它们的患者创造有针对性的治疗的最终目标。