Development of new peptide based NIR probe conjugates for specifically and selectively detecting amyloid early biomarkers

开发新的基于肽的近红外探针缀合物，用于特异性和选择性地检测淀粉样蛋白早期生物标志物

• 批准号: 505429707
• 负责人: Professor Dr. Norbert Sewald
• 金额: --
• 依托单位: Arbeitskreis Organische Chemie III
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505429707?language=en
• 关键词: Development; new; peptide; based; NIR

FluPepDye aims to provide new selective NIR-fluorescent cyclopeptides for specifically detecting early biomarkers of distinct amyloid pathologies and to translate amyloid-binding fluorophores into useful research or clinical tools for aiding the early and reliable diagnosis of amyloid-related diseases. The project principally focuses on Amyloid β(1-42) peptide (Aβ1-42), involved in Alzheimer’s Disease (AD), and it aims to extend the employed modulable approach to other amyloidogenic proteins such as α-synuclein, tau and hIAPP, involved in other pathologies. While more than 20 amyloid diseases (such as neurodegenerative diseases and type II Diabetes) are known and involve more than 30 amyloid proteins, no early diagnostic tools are currently available for any of these diseases. It is crucial to establish early and precise diagnostics of the type of degeneration before specific symptoms of the disease appear, because when the clinical symptoms are present, the destruction of the target organs and cells (neurons in neurodegenerative diseases and pancreatic β-cells in diabetes) is irreversible. Several efforts have been made in the field of bioimaging using non-invasive NIR probes in the frame of neurodegenerative diseases, particularly for AD diagnosis. Despite their favourable features for their in vivo application, their translation into the clinical practice remains challenging and further optical improvements and technological evolutions are still needed. To our knowledge, none of them has been designed and proven to be specific for only one type of amyloid protein. Furthermore, probes able to detect selectively only soluble oligomers at the pre-clinical stage of neurodegeneration have not been reported to date. This research project will focus on the design, synthesis and evaluation of new peptide based NIR probe conjugates. These new fluorescent molecules are conceived to have suitable emission wavelengths with turn-on optical properties, selectivity for one specific amyloid protein and its soluble early aggregate species, high stability in biological environments, and good permeability across membranes. The new peptide-based probe conjugates will be composed by three elements: a cyclopeptide as recognition element that will drive the selectivity for a specific amyloid protein and for oligomer species, a tryptophan as anchor element for conjugation by palladium catalysed cross-coupling reactions and a fluorescent probe as tracer element providing tailored NIR fluorescence. These probes will be evaluated in biophysical assays to get information on their fluorescent properties, their affinity of binding, their selectivity, their metabolic stability, and their membrane permeability.

FluPepDye旨在提供新的选择性近红外荧光环肽，用于特异性检测不同淀粉样病变的早期生物标记物，并将淀粉样蛋白结合荧光团转化为有用的研究或临床工具，以帮助淀粉样蛋白相关疾病的早期和可靠诊断。该项目主要集中在与阿尔茨海默病(AD)有关的淀粉样蛋白β(1-42)肽(Aβ1-42)，旨在将所采用的可调节方法扩展到其他与其他病理相关的淀粉样蛋白，如α-突触核蛋白、tau和hIAPP。虽然已知有20多种淀粉样疾病(如神经退行性疾病和II型糖尿病)，涉及30多种淀粉样蛋白，但目前还没有针对这些疾病的早期诊断工具。在疾病的特定症状出现之前，对退行性疾病的类型建立早期和准确的诊断是至关重要的，因为当临床症状出现时，靶器官和细胞(神经退行性疾病中的神经元和糖尿病中的胰腺β细胞)的破坏是不可逆转的。在神经退行性疾病的框架内，使用非侵入性近红外探头进行生物成像，特别是在AD诊断方面，已经做出了一些努力。尽管它们具有在体内应用的有利特征，但它们转化为临床实践仍然具有挑战性，仍然需要进一步的光学改进和技术进步。据我们所知，它们中没有一个是被设计和证明只针对一种类型的淀粉样蛋白的。此外，到目前为止，还没有报道能够选择性地检测神经变性临床前阶段的可溶低聚物的探针。本研究项目将致力于新型多肽类近红外探针偶联物的设计、合成和评价。这些新的荧光分子被认为具有合适的发射波长，具有开启的光学性质，对一种特定的淀粉样蛋白及其可溶的早期聚集物种具有选择性，在生物环境中具有高度的稳定性，以及良好的跨膜渗透性。新的基于多肽的探针结合物将由三种元素组成：环肽作为识别元素，将驱动特定淀粉样蛋白和低聚物物种的选择性；色氨酸作为锚定元素，用于钯催化的交叉偶联反应；以及荧光探针，作为提供定制近红外荧光的示踪元素。这些探针将在生物物理分析中进行评估，以获得有关它们的荧光特性、结合亲和力、选择性、代谢稳定性和膜通透性的信息。