Novel opioid peptides for nose to brain delivery

用于鼻子到大脑输送的新型阿片肽

• 批准号: 9335835
• 负责人: PREDRAG CUDIC
• 金额: $ 23.36万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335835
• 关键词: Accounting; Adhesives; Adsorption; Affect; Affinity; Agonist; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Binding; Biological; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Brain Diseases; Bypass; Calorimetry; Caring; Cattle; Cells; Central Nervous System Diseases; Collaborations; Coupled; Cyclic Peptides; Development; Diffusion; Disease; Drug Delivery Systems; Drug Transport; Enkephalins; Evaluation; Exhibits; Fucose; Goals; Homing; Hospitalization; Hydrophobicity; In Vitro; Intranasal Administration; Lead; Lectin; Libraries; Ligands; Measurable; Meningitis; Metabolic; Methods; Migraine; Modeling; Modification; Molecular Weight; Mucociliary Clearance; Mus; Nasal cavity; Nose; Olfactory Epithelium; Olfactory Mucosa; Olfactory Nerve; Opioid; Opioid Peptide; Opioid Receptor; Parents; Parkinson Disease; Peptides; Periodicity; Pharmaceutical Preparations; Pilot Projects; Positioning Attribute; Process; Property; Proteins; Randomized; Research; Route; S Phase; Scanning; Schizophrenia; Series; Solid; Structure; Structure of mucous membrane of nose; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Titrations; addiction; analog; asialofetuin; base; blood cerebrospinal fluid barrier; combinatorial; design; disability; drug discovery; effective therapy; experimental study; improved; in vivo; innovation; insight; ionization; mouse model; nervous system disorder; novel; novel strategies; novel therapeutics; peptide drug; preclinical development; public health relevance; residence; scaffold; screening; success; sugar; tool

 DESCRIPTION (provided by applicant): Diseases of the central nervous system such as schizophrenia, meningitis, migraine, Parkinson's and Alzheimer's disease, along with other neurological disorders, such as addiction, require delivery of the drug to the brain for effective treatment. However, treatment for these diseases is still a challenge due to the inability of many drugs, especially hydrophobic and large molecular weight drugs such as peptides and proteins, to cross the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB). Direct delivery of therapeutic agents from the nasal cavity into the brain bypasses the BBB and BCB and offers a viable alternative to conventional strategies for brain targeting, but remains a major challenge due to the lack of efficient delivery system. To increase intranasal delivery of therapeutic peptides to the brain we designed a novel strategy based on grafting a bioactive amino acid sequence onto the scaffold of cyclic peptide odorranalectin (OL) that exhibits lectin-like properties. OL can specifically bind to L-fucose, which is widely distributed on the olfactory epithelium of nasal mucosa, suggesting a possibility for extending its residence time in the nasal cavity, thereby allowing its increased adsorption. As a proof-of-concept, we have successfully synthesized a novel cyclic opioid peptide DADLE-OL by grafting the sequence of a known mixed and agonist, [D-Ala2, D-Leu5] enkephalin (DADLE), into the OL scaffold. In our piot studies we have demonstrated that DADLE-OL can be delivered via the nasal route to the mouse brain and that this novel opioid peptide can produce biological effects following the intranasal administration in mice. To further validate our approach we propose to: (a) prepare a focused positional scanning combinatorial library (PSCL) based on the OL scaffold (Aim 1), (b) screen the prepared PSCL for affinity toward andopioid receptors as model trgets for the treatment of brain disorders and assess the most selective and potent analogs abilities to bind L-fucose for bio-adhesive purpose (Aim 2), and (c) assess the selected OL analogs ability to be transported from nose-to-brain in a mouse model and produce biological effects (Aim 3). The information gained from the proposed research will assist us in establishing the lead structure for further modification and development of novel therapeutic agents for the treatment of CNS diseases.

 描述（由申请人提供）：中枢神经系统疾病，如精神分裂症、脑膜炎、偏头痛、帕金森病和阿尔茨海默病，以及其他神经系统疾病，如成瘾，需要将药物输送到大脑进行有效治疗。由于许多药物，特别是疏水性和大分子量药物，如肽和蛋白质，无法穿过血脑屏障（BBB）和血脑脊液屏障 (BCB) 将治疗药物从鼻腔直接输送至大脑，绕过 BBB 和 BCB，为传统的脑靶向策略提供了一种可行的替代方案，但仍然是一种主要的治疗方法。 为了增加治疗性肽向大脑的鼻内递送，我们设计了一种新策略，将生物活性氨基酸序列移植到具有凝集素样高效特性的环肽臭凝素 (OL) 支架上。 OL能特异性结合L-岩藻糖，L-岩藻糖广泛分布于嗅觉上 鼻粘膜上皮细胞，表明有可能延长其在鼻腔中的停留时间，从而增加其吸收。作为概念验证，我们通过嫁接 a 序列成功合成了一种新型环状阿片肽 DADLE-OL。在我们的初步研究中，将已知的混合  和  激动剂 [D-Ala2, D-Leu5] 脑啡肽 (DADLE) 加入到 OL 支架中。我们已经证明 DADLE-OL 可以通过鼻腔途径递送至小鼠大脑，并且这种新型阿片肽可以在小鼠鼻内给药后产生生物效应。为了进一步验证我们的方法，我们建议：（a）准备一个集中的。基于 OL 支架的位置扫描组合文库 (PSCL)（目标 1），(b) 筛选制备的 PSCL 的亲和力  和  鸦片受体作为治疗脑部疾病的模型靶标，并评估最具选择性和最有效的类似物结合 L-岩藻糖以实现生物粘附目的的能力（目标 2），以及 (c) 评估选择的 OL 类似物能够在小鼠模型中从鼻子转运到大脑并产生生物效应（目标 3）。将帮助我们建立先导结构，以进一步修改和开发治疗中枢神经系统疾病的新型治疗药物。

项目成果

Solid-Phase Synthesis of the Bicyclic Peptide OL-CTOP Containing Two Disulfide Bridges, and an Assessment of Its In Vivo μ-Opioid Receptor Antagonism after Nasal Administration.

含有两个二硫桥的双环肽 OL-CTOP 的固相合成，及其鼻腔给药后体内 μ-阿片受体拮抗作用的评估。

• 发表时间: 2023-02-15
• 作者: Rayala, Ramanjaneyulu;Tiller, Annika;Majumder, Shahayra A;Stacy, Heather M;Eans, Shainnel O;Nedovic, Aleksandra;McLaughlin, Jay P;Cudic, Predrag
• 通讯作者: Cudic, Predrag