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: 9035693
• 负责人: PREDRAG CUDIC
• 金额: $ 22.1万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035693
• 关键词: Accounting; Adhesives; Adsorption; Affect; Affinity; Agonist; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Binding; Biological; Biological Assay; 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; 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; Work; addiction; analog; asialofetuin; base; blood cerebrospinal fluid barrier; combinatorial; design; disability; drug discovery; effective therapy; improved; in vivo; innovation; insight; ionization; mouse model; nervous system disorder; novel; novel strategies; novel therapeutics; peptide drug; pre-clinical; public health relevance; research study; 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、帕金森氏病和阿尔茨海默氏病，沿着其他神经系统疾病，如成瘾，需要将药物递送至大脑以进行有效治疗。然而，这些疾病的治疗仍然是一个挑战，由于许多药物，特别是疏水性和大分子量的药物，如肽和蛋白质，不能通过血脑屏障（BBB）和血脑脊液屏障（BCB）。将治疗剂从鼻腔直接递送到脑中绕过BBB和BCB，并提供了脑靶向的常规策略的可行替代方案，但仍然是脑靶向的主要障碍。 由于缺乏有效的交付系统，这是一个挑战。为了增加鼻内递送治疗肽到大脑，我们设计了一种基于将生物活性氨基酸序列移植到具有凝集素样性质的环肽odorranalectin（OL）的支架上的新策略。OL可以特异性结合L-岩藻糖，而L-岩藻糖广泛分布在嗅觉器官上， 鼻粘膜上皮细胞，表明延长其在鼻腔中的停留时间的可能性，从而允许其增加的吸附。作为概念验证，我们已经成功地合成了一种新的环状阿片肽DADLE-OL，通过将已知的混合阿片肽和阿片肽激动剂[D-Ala 2，D-Leu 5]脑啡肽（DADLE）的序列移植到OL支架中。在我们的初步研究中，我们已经证明DADLE-OL可以通过鼻途径递送到小鼠脑，并且这种新型阿片肽在小鼠鼻内给药后可以产生生物学效应。 为了进一步验证我们的方法，我们建议：（a）制备基于OL支架的聚焦位置扫描组合文库（PSCL）（目的1），（B）筛选制备的PSCL对作为治疗脑疾病的模型靶点的β-葡聚糖和β-葡聚糖阿片受体的亲和力，并评估最具选择性和有效的类似物结合L-岩藻糖用于生物粘附目的的能力（目的2），和（c）评估所选OL类似物在小鼠模型中从鼻转运至脑并产生生物效应的能力（目的3）。 从拟议的研究中获得的信息将有助于我们建立先导结构，用于进一步修饰和开发用于治疗CNS疾病的新型治疗药物。