Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development.
Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development.
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DOI：
10.3390/cells11223629
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发表时间：
2022-11-16
期刊：
影响因子：
6
通讯作者：
Salton, Stephen R.
中科院分区：
文献类型：
--
作者：
Bose, Meenakshi;Quipildor, Gabriela Farias;Ehrlich, Michelle E.;Salton, Stephen R.
中枢神经系统（CNS）是人体所有器官系统中，传统小分子药物研发的失败率最高，根据疾病研究领域的不同，失败率从80%到100%不等。这导致制药行业普遍放弃中枢神经系统疾病的研发，尽管神经退行性疾病的诊断有所增加，并且脑损伤、中风、神经发育障碍和神经精神疾病仍然缺乏足够的治疗选择。然而，随着复杂的生物信息学和基因组工具的发展，新方法被用来探索基于肽的疗法来操纵内源性途径和靶标，包括“不可成药”的细胞内蛋白质-蛋白质相互作用（PPI）。由于传统口服和全身给药方法引起的全身脱靶效应和生物利用度差，基于肽的疗法的开发此前曾被拒绝。然而，有针对性的鼻到脑或鼻内（IN）方法已经开始出现，允许通过三叉神经和嗅觉神经通路进行中枢神经系统特异性治疗药物的递送，为改进全身药物递送的替代方案奠定了基础。在这里，我们回顾了十几种在神经退行性疾病（阿尔茨海默病、帕金森病）、神经精神疾病（抑郁症、创伤后应激障碍、精神分裂症）和神经发育障碍（自闭症）的临床前和临床开发中具有前景的 IN 肽疗法，其中胰岛素、NAP（达武奈肽）、IGF-1、PACAP、NPY、催产素和 GLP-1 激动剂是其中最突出的。
The central nervous system (CNS) has, among all organ systems in the human body, the highest failure rate of traditional small-molecule drug development, ranging from 80–100% depending on the area of disease research. This has led to widespread abandonment by the pharmaceutical industry of research and development for CNS disorders, despite increased diagnoses of neurodegenerative disorders and the continued lack of adequate treatment options for brain injuries, stroke, neurodevelopmental disorders, and neuropsychiatric illness. However, new approaches, concurrent with the development of sophisticated bioinformatic and genomic tools, are being used to explore peptide-based therapeutics to manipulate endogenous pathways and targets, including “undruggable” intracellular protein-protein interactions (PPIs). The development of peptide-based therapeutics was previously rejected due to systemic off-target effects and poor bioavailability arising from traditional oral and systemic delivery methods. However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer’s, Parkinson’s), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (autism), with insulin, NAP (davunetide), IGF-1, PACAP, NPY, oxytocin, and GLP-1 agonists prominent among them.
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影响因子：
3.7
作者：
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Benedict, Christian
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影响因子：
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作者：
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通讯作者：
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