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Richard L Redman1, Isaac J Krauss1
1Department of Chemistry, Brandeis University, 415 South Street MS 015, Waltham, Massachusetts 02454, United States.
Journal of the American Chemical Society
|June 7, 2021
概括
我们开发了一种使用定向进化的新方法, 这种平台设计了最佳的甘氨酸集群以实现高亲和度的结合,通过向HIV抗体来证明这一点.
科学领域:
- 生物化学
- 分子生物学
- 药物发现
背景情况:
- 碳水化合物结合蛋白 (CBPs) 在生物过程和疾病中至关重要.
- 高亲和性相互作用通常依赖于多价值性,其中多个甘氨酸与蛋白质结合.
- 开发有效的基于碳水化合物的疗法需要精确控制糖呈现.
研究的目的:
- 建立一个设计多价值碳水化合物集群配体的新平台.
- 用定向进化来优化稳定的骨干上的糖聚类.
- 通过选择针对特定广泛中和抗体的配体来验证平台.
主要方法:
- 使用定向进化来选择功能性RNA序列.
- 设计血清稳定的2'-改RNA (F-RNA) 骨干以呈现甘氨酸.
- 选一个大序列池 (∼10^13) 寻找高亲缘关系的结合剂.
主要成果:
- 成功选择了对HIV抗体2G12的高亲和度的寡甘 (Man9) .
- 在13至36nM的范围内达到结合亲和度.
- 证明了F-RNA平台在产生强大的多价值连接体方面的有效性.
结论:
- 定向进化平台可以合理设计多价碳水化合物配体.
- 这种方法对于开发高亲和度结合剂对抗具有挑战性的标,如广泛中和抗体是有效的.
- 在治疗应用中,F-RNA骨干提供了稳定性和最佳呈现.
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