通过自动流合成技术实现原生和镜像瘤坏死因子-α的快速产生
Ahmet Yesilcimen1, Alex J Callahan1, Tara L Travaline2
1Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
The Journal of organic chemistry
|September 10, 2024
概括
研究人员开发了一种新的合成瘤亡因子-α (TNF-α) 的方法,使用自动化快流合成和原生化学结合. 这种方法产生了功能合成的TNF-α,为开发稳定,不太免疫的治疗方法提供了新的途径.
科学领域:
- 生物化学 生化学
- 蛋白质合成 蛋白质合成
- 药物发现 药物发现 药物发现
背景情况:
- 瘤坏死因子-α (TNF-α) 是免疫反应的关键调节者.
- 提升的TNF-α与各种疾病有关,使其抑制成为治疗目标.
- 目前的TNF-α抑制剂面临着免疫性和体内疗效方面的挑战.
研究的目的:
- 开发一种用于合成全长TNF-α的新方法.
- 为治疗开发生产稳定且免疫性较低的TNF-α类似物.
- 建立一种可通用的协议,用于合成现有方法难以处理的蛋白质.
主要方法:
- 利用自动化快流合成 (AFPS) 来产生片段.
- 采用原生化学联结 (NCL),将AFPS生成的片段连接成全长的TNF-α.
- 通过高通量选优化氧化折叠条件以获得功能性蛋白质.
主要成果:
- 成功合成了毫克数量的L-和D-TNF-α (高达5.5毫克,约28%的收益率).
- 获得的功能合成TNF-α具有与重组TNF-α相似的特征.
- 证明了产生镜像D-TNF-α的可行性.
结论:
- 联合AFPS和NCL策略为合成TNF-α提供了一条有效的途径.
- 这种方法有助于创建新型蛋白质疗法,其稳定性提高,免疫性降低.
- 这种方法为合成具有挑战性的蛋白质提供了一个可通用的协议,推动了治疗发现.
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