Novel opioid peptides for nose to brain delivery

 描述(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、帕金森氏症和阿尔茨海默病，以及其他神经疾病，如成瘾，需要将药物输送到大脑进行有效治疗。然而，这些疾病的治疗仍然是一个挑战，因为许多药物，特别是疏水性和大分子药物，如多肽和蛋白质，无法跨越血脑屏障(BBB)和血脑脊液屏障(BCB)。将治疗剂从鼻腔直接输送到大脑，绕过了血脑屏障和血脑屏障，为脑靶向治疗提供了一种可行的替代策略，但仍是主要的 由于缺乏有效的交付系统，这是一项挑战。为了增加治疗性多肽的鼻腔输送到大脑，我们设计了一种新的策略，将一个生物活性氨基酸序列嫁接到具有凝集素样属性的环状多肽odorranalectin(OL)支架上。醇能与广泛分布在嗅觉上的L岩藻糖结合 在鼻腔粘膜上皮细胞，表明可能延长其在鼻腔内的滞留时间，从而增加其吸附。作为概念验证，我们通过将已知的混合和激动剂[D-丙氨酸，D-亮氨酸]脑啡肽(DADLE)的序列嫁接到OL支架上，成功地合成了一种新型的环状阿片肽DADLE-OL。在我们的PIOT研究中，我们已经证明了DADLE-OL可以通过鼻腔途径传递到小鼠的大脑，并且这种新的阿片肽可以在小鼠鼻腔给药后产生生物学效应。为了进一步验证我们的方法，我们建议：(A)制备一个基于OL支架的聚焦位置扫描组合文库(目标1)，(B)筛选制备的位置扫描组合文库以与和阿片受体亲和力作为治疗脑疾病的模型目标，并评估最选择性和最有效的类似物结合L-岩藻糖用于生物黏附目的(目标2)，以及(C)评估选定的OL类似物在小鼠模型中从鼻子转运到大脑并产生生物效应的能力(目标3)。从拟议的研究中获得的信息将有助于我们建立进一步修饰和开发治疗中枢神经系统疾病的新型治疗剂的先导结构。

 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.