Chemistry of Probes and Therapeutics

探针和治疗化学

基本信息

批准号：
8727720
负责人：
PAUL Anthony WENDER
金额：
$ 17.19万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727720
关键词：
Address Animals Area Binding Cancer Detection Cells Chemistry Clinical Clinical Trials Colon Cyclosporine Detection Development Disease Docking Drug Delivery Systems Drug usage Early Diagnosis Endoscopy Evaluation Figs - dietary Florida Gastrointestinal tract structure Goals High Performance Computing Human Image Imagery Label Laboratories Lead Lung Magnetism Malignant neoplasm of gastrointestinal tract Metals Methodology Methods Molecular Molecular Probes Neoplasms Paclitaxel Peptides Pharmaceutical Preparations Phase Plasmids Precancerous Polyp Premalignant Procedures Process Proteins Psoriasis Reagent Research Personnel SN-38 Sirolimus Small Interfering RNA Solvents Specificity Structure Survival Rate System Technology Therapeutic Therapeutic Agents Time Tissues Topical agent Transcend Transgenic Animals Translating Universities Work base cancer diagnosis cancer therapy chemical group combinatorial controlled release design experience fluorophore heuristics improved inhibitor/antagonist innovation molecular dynamics molecular imaging molecular transporter multimodality novel novel therapeutics optical imaging parallel processing particle programs small molecule tool uptake

项目摘要

7.2.1. Core A. Chemistry of probes and therapeutics Core Leader: Paul Wender Investigators: Lawrence Marnett, David Ostrov Aim 1: Review probe designs for the major projects and task-specific projects including those based on peptides and cox-2 inhibitors, and optimize conjugation chemistries for fluorescent and Raman tags (Fig 25). It is generally accepted that early detection leads to improved survival rates in the treatment of cancers. Detection of cancers and precancerous polyps in the gastrointestinal tract has been improved with endoscopy procedures, but this approach can miss difficult to observed tissue and flat neoplasias. In addition for some situations the difference between normal and precancerous tissue is only detectable at the molecular level. This necessitates the use of molecular probes for visualization of tissue differences. The Wender lab has considerable expertise in the innovation and use of drug/probe delivery systems, which includes the development of peptide and probe chemistry, as well as methods for their conjugation and evaluation in cells and in animals. This expertise will be employed in the design and synthesis of novel probe conjugates, as well as the development and even invention of synthetic methods as necessary. A variety of linkage strategies to make both non-releasable and releasable compounds as well as selectively releasable conjugates has been developed. The laboratories offer considerable experience in the design, synthesis, and evaluation of molecular probes that are indispensable tools for molecular imaging strategies. A significant challenge in the development of probes for optical imaging is in the attachment of labels for detection. The selection of fluorophores .and how they are conjugated to specific probes can drastically alter the specificity and usefulness of selected peptides or small molecules. We aim to address this challenge by using structure-based molecular dynamic simulations to assess the preferred orientation of the probe bound to the target protein. This process is adapted from the molecular docking method we utilize in the high-throughput mode to select small molecules specific for target proteins (by parallel processing using DOCK6 at the University of Florida High Performance Computing Center). After determining the most likely orientation of the probe bound to the target protein (Fig. 25), solvent exposed atoms in the probe are selected as points of attachment for the label (Fig. 25). Real-time Automated Combinatorial Heuristic Enhancement of Lead compounds, RACHEL (Tripos, Inc.) is a drug optimization package designed to optimize weak binding lead compounds in an automated, combinatorial fashion. We routinely use RACHEL to add chemical groups, such as fluorophores, to lead compounds that bind with Kd values in the micromolar range in order to increase their specific activities (Fig. 25). This process can be applied to 5ROX and a large number of potential fluorophores to maximize the likelihood of identifying optimized labeled probes that retain specificity. Aim 2: Design next generation therapeutic agents and develop conjugates with directed delivery and controlled release. The Wender lab has considerable experience with the design, synthesis and evaluation of probe conjugates that enable or enhance cell and tissue entry. Procedures and systems have been developed that allow for quantification of uptake in real time in cells and in transgenic animals. These studies have been translated into the development of conjugates for drug delivery, including studies that have progressed to phase II human clinical trials. Much of this work has been applied the delivery of a plethora of therapeutics via a molecular transporter, most specifically but not limited to octaarginine. This molecular transporter has been used to deliver therapeutic agents such as taxol, cyclosporine A, SN-38, rapamycin, peptides, proteins, siRNA, plasmid DMA, metals, imaging agents and even magnetic particles. A variety of release mechanisms have been developed. The transporter technology and bioreleasable linker strategies developed in our laboratories have numerous applications which transcend the focus of this particular effort and could have applications for the entire field of drug delivery as well as conjugation chemistry. With the growing importance of selectivity in the delivery of therapeutic agents, we can apply methods previously developed in our lab related to drug delivery and expand on this methodology to realize the goal of selective delivery to gastrointestinal cancers, as well as other diseases. All facets of this application that rely on molecular detection and visualization can be facilitated and enhanced through access to design and synthetic expertise available in the core laboratory. Aim 3: Work with investigators and the FDA to first develop and then get approval for new reagents that can be used in the Gl tract for imaging and therapy. Development of new selective probe and therapeutic agents for the detection and treatment of gastrointestinal cancers is intended for eventual application in a clinical setting. The Wender lab has experience in this area with the development of octaarginine-cyclosporine A agents for the topical treatment of psoriasis, with conjugates advancing into Phase II human clinical trials. Studies have also been advanced based on IP, ocular, buccal, and lung drug administration, procedures that not unlike the proposed colon studies involve local administration. This expertise is available to enable and facilitate the design, synthesis, and evaluation of new probes and drug conjugates as needed to achieve the aims of the program.

7.2.1.核心 A. 探针和治疗的化学核心领导人：保罗·文德调查员：劳伦斯·马内特、大卫·奥斯特罗夫目标 1：审查主要项目和特定任务项目的探针设计，包括基于肽和 cox-2 抑制剂，并优化荧光和拉曼标签的缀合化学（图 25）。人们普遍认为，早期检测可以提高癌症治疗的生存率。胃肠道癌症和癌前息肉的检测得到了改善内窥镜检查程序，但这种方法可能会错过难以观察的组织和扁平肿瘤。在此外，在某些情况下，正常组织和癌前组织之间的差异只能在分子水平。这需要使用分子探针来可视化组织差异。 Wender 实验室在药物/探针输送系统的创新和使用方面拥有丰富的专业知识，其中包括肽和探针化学的发展，以及它们的缀合方法以及在细胞和动物中的评估。这些专业知识将用于新颖的设计和合成探针缀合物，以及必要时合成方法的开发甚至发明。一个多种连接策略来制备不可释放和可释放的化合物以及已开发出可选择性释放的缀合物。实验室在以下方面提供了丰富的经验分子探针的设计、合成和评估是分子生物学研究不可或缺的工具成像策略。光学成像探针开发中的一个重大挑战是为探针添加标签检测。荧光团的选择以及它们如何与特定探针缀合可以极大地改变改变所选肽或小分子的特异性和有用性。我们的目标是解决这个问题通过使用基于结构的分子动力学模拟来评估优先方向的挑战探针与目标蛋白结合。这个过程改编自我们的分子对接方法利用高通量模式来选择针对靶蛋白的特异性小分子（通过平行使用佛罗里达大学高性能计算中心的 DOCK6 进行处理）。确定探针与目标蛋白结合的最可能方向后（图 25），溶剂选择探针中暴露的原子作为标记的附着点（图25）。即时的先导化合物的自动组合启发式增强，RACHEL (Tripos, Inc.) 是一种药物优化包旨在以自动化、组合时尚。我们通常使用 RACHEL 添加化学基团，例如荧光团，以引导与微摩尔范围内的 Kd 值结合以增加其比活性的化合物（图25）。该过程可应用于 5ROX 和大量潜在荧光团，以最大限度地提高识别保留特异性的优化标记探针的可能性。目标 2：设计下一代治疗剂并开发具有定向递送和受控释放。 Wender实验室在探针的设计、合成和评估方面拥有丰富的经验能够或增强细胞和组织进入的缀合物。程序和系统已经制定允许对细胞和转基因动物的摄取进行实时定量。这些研究有已转化为药物递送缀合物的开发，包括已经进行的研究进入II期人体临床试验。这项工作的大部分已应用于交付过多的经由分子转运蛋白的治疗，最具体地但不限于八精氨酸。这个分子转运蛋白已被用于递送治疗剂，例如紫杉醇、环孢菌素 A、SN-38、雷帕霉素、肽、蛋白质、siRNA、质粒 DMA、金属、显像剂甚至磁性颗粒。各种释放机制已经制定。转运蛋白技术和生物可释放连接体策略我们实验室开发的许多应用超出了这个特定的重点努力并可应用于整个药物输送和缀合化学领域。随着选择性在治疗药物递送中的重要性日益增加，我们可以应用以下方法我们实验室之前开发了与药物输送相关的方法，并扩展了该方法以实现目标选择性递送胃肠道癌症以及其他疾病。该应用程序的所有方面依赖于分子检测和可视化的技术可以通过获取核心实验室提供设计和合成专业知识。目标 3：与研究人员和 FDA 合作，首先开发新产品，然后获得批准可用于胃肠道成像和治疗的试剂。开发用于检测和治疗的新型选择性探针和治疗剂胃肠道癌症旨在最终应用于临床。文德实验室有在开发用于局部用药的八精氨酸-环孢素 A 制剂方面拥有该领域的经验治疗牛皮癣，结合物进入 II 期人体临床试验。研究还基于IP、眼部、颊部和肺部给药的先进技术，这些程序与拟议的结肠研究涉及局部给药。这种专业知识可用于启用和促进根据需要设计、合成和评估新的探针和药物缀合物，以实现以下目标程序。