发现具有抗百草枯毒性神经保护活性的混合甘草酸盐共轭物

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sara C. Silva-Reis, Vera M. Costa, Daniela Correia da Silva, David M. Pereira, Xavier Cruz Correia, Xerardo García-Mera, José E. Rodríguez-Borges and Ivo E. Sampaio-Dias
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引用次数: 0

摘要

神经退行性疾病由一系列不同的病症组成,影响着全球数百万人,对发达国家和发展中国家的健康都造成了重大负担。由于目前尚无可改变疾病的治疗方法,开发有效的神经治疗药物成为健康领域的当务之急。在这项工作中,报告了一系列新的甘草酸神经肽共轭物,以确定环状收缩和神经保护活性之间的相互作用。为此,除了用相关的活性药物成分(APIs)(即金刚烷胺、美金刚和(R)-1-氨基茚烷)对谷氨酸残基进行功能化外,还使用了(1R,3S,4S)-2-氮杂降冰片烷-3-羧酸作为L-脯氨酸和L-哌啶酸的替代物。使用未分化的 SH-SY5Y 细胞,与金刚烷胺功能化的共轭物 14a 和 15a 能显著减少蛋白质的聚集,其中 15a 的效果优于甘丙肽(增强 2 倍,p < 0.05)以及甘丙肽和金刚烷胺的等摩尔混合物(p < 0.0001)。另一方面,在 SH-SY5Y 分化细胞中,与 (R)-1-aminoindane 功能化的共轭物 18c 抵消了百草枯引起的毒性(p < 0.0001),而 Glypromate 则加剧了神经毒性。总之,这项研究为甘丙酸酯的研究增添了新的见解,证明了化学共轭和环状收缩是针对不同神经毒性刺激调整神经保护反应的有效策略,为开发新的神经治疗药物铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of hybrid Glypromate conjugates with neuroprotective activity against paraquat-induced toxicity†

Discovery of hybrid Glypromate conjugates with neuroprotective activity against paraquat-induced toxicity†

Discovery of hybrid Glypromate conjugates with neuroprotective activity against paraquat-induced toxicity†

Neurodegenerative disorders comprise a series of heterogeneous conditions that affect millions of people worldwide, representing a significant health burden in both developed and developing countries. Without disease-modifying treatments currently available, the development of effective neurotherapeutics is a health priority. In this work, a new series of peptide-conjugates of the Glypromate neuropeptide is reported to determine the interplay of annular constriction and neuroprotective activity. To this end, (1R,3S,4S)-2-azanorbornane-3-carboxylic acid was used as an L-proline and L-pipecolic acid surrogate in addition to functionalization of the glutamate residue with relevant active pharmaceutical ingredients (APIs), namely amantadine, memantine, and (R)-1-aminoindane. Using non-differentiated SH-SY5Y cells, conjugates 14a and 15a, functionalized with amantadine, significantly reduced protein aggregation, with 15a outperforming both Glypromate (2-fold enhancement, p < 0.05) and an equimolar mixture of Glypromate and amantadine (p < 0.0001). On the other hand, in SH-SY5Y differentiated cells, conjugate 18c functionalized with (R)-1-aminoindane counteracted the toxicity elicited by paraquat (p < 0.0001), while Glypromate was found to exacerbate the neurotoxicity. Altogether, this work adds new insights into Glypromate research by demonstrating that chemical conjugation and annular constriction are effective strategies to tune neuroprotective responses against different neurotoxic stimuli, paving the way for the development of new neurotherapeutics.

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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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