发现了针对PCSK9上诱导适合口袋的截断循环
Philipp Grosche1, Alec N Flyer2, Raphael Gattlen1
1Novartis Biomedical Research, Fabrikstrasse 2, Novartis Campus, 4056, Basel, Switzerland.
ChemMedChem
|October 22, 2024
概括
研究人员通过降低体大小和电荷来优化PCSK9抑制剂,提高它们作为控制胆固醇水平的口服药物的潜力. 这些修改后的在破坏PCSK9/LDL-R相互作用方面保持有效性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 蛋白转化酶亚提利辛/凯辛9型 (PCSK9) 是血低密度脂蛋白胆固醇 (LDL-C) 的关键调节剂.
- PCSK9促进肝脏中的LDL受体 (LDL-R) 的降解,增加LDL-C水平.
- 以前的努力产生了13-mer循环,可以抑制PCSK9/LDL-R相互作用,但有局限性.
研究的目的:
- 为了开发更小的,口服生物可用的PCSK9抑制剂.
- 修改现有的循环,以改善它们的药物性质.
- 探索用于PCSK9抑制的替代性基架.
主要方法:
- 基于结构的13-mer循环的修改.
- 生物化学和细胞测试以评估蛋白质与蛋白质相互作用 (PPI) 的抑制.
- mRNA-的显示选,以识别新的结剂.
主要成果:
- 截断后的中性保留了完全的PCSK9/LDL-R PPI抑制功能.
- 新的mRNA-片查发现了与PCSK9.9结合的8和9默尔化合物.
- 这些较小的与PCSK9诱导的适合口袋的相互作用不同.
结论:
- 基于结构的设计可以产生更小,功能性的PCSK9抑制剂.
- 为了减少体大小和复杂性,存在多种策略.
- 这些发现为开发针对PCSK9.9的小分子口服药物铺平了道路.
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