Novel opioid peptides for nose to brain delivery

用于鼻子到大脑输送的新型阿片肽

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由适用提供）：中枢神经系统的疾病，例如精神分裂症，脑膜炎，偏头痛，帕金森氏症和阿尔茨海默氏病，以及其他神经系统疾病，例如成瘾，都需要将药物递送到大脑中才能有效治疗。然而，由于许多药物，尤其是疏水性和大分子量药物（如辣椒和蛋白质）无法跨越血脑屏障（BBB）和血脑屏室液体屏障（BCB），因此对这些疾病的治疗仍然是一个挑战。将治疗剂从鼻腔直接输送到大脑绕过BBB和BCB，并为大脑靶向的常规策略提供了可行的替代方案，但仍然是主要的挑战由于缺乏有效的交付系统。为了增加鼻内热肽向大脑的递送，我们设计了一种新型策略，基于将生物活性氨基酸序列移植到表现出类似讲座特性的环状肽odorranalectin（ol）的支架上。 OL可以特异性结合L-凝血液，该结合在嗅觉上广泛分布鼻粘膜上皮，表明有可能在鼻腔中延长其停留时间，从而允许其吸附增加。作为概念验证，我们通过将已知混合的和仪的序列（d-ala2，d-leu5] enkephalin（dadle）接管到ol caffold中，我们成功地合成了一种新型的环状阿片类肽dadle-ol。在我们的Piot研究中，我们已经证明可以通过鼻腔途径传递到小鼠脑，而这种新型的阿片类肽可以在小鼠内鼻内给药后产生生物学作用。为了进一步验证我们的方法，我们提出：（a）基于OL脚手架（目标1），（b）筛选准备好的PSCL的pscl对和 （c）评估所选的类似物能够从小鼠模型中从鼻子到脑运输并产生生物学效应的能力（AIM 3）。从拟议的研究中获得的信息将有助于我们建立铅结构，以进一步修改和开发新型治疗剂以治疗中枢神经系统疾病。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.

DOI：
10.3390/molecules28041822
发表时间：
2023-02-15
期刊：
MOLECULES
影响因子：
4.6
作者：
Rayala, Ramanjaneyulu;Tiller, Annika;Majumder, Shahayra A. A.;Stacy, Heather M. M.;Eans, Shainnel O. O.;Nedovic, Aleksandra;McLaughlin, Jay P. P.;Cudic, Predrag
通讯作者：
Cudic, Predrag