基于机制的血清蛋白酶宏循环抑制剂
Vishnu C Damalanka1, Victoria Banas1, Paolo De Bona1
1Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, Saint Louis, Missouri 63110, United States.
新的宏环蛋白酶抑制剂克服了类药物限制. 这些化合物显示出更好的选择性,稳定性和药理动力学特性,为药物发现提供了一种新的策略.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 生物化学 生物化学
背景情况:
- 基于的蛋白酶抑制剂面临的挑战包括细胞透性差,代谢不稳定性和快速清除.
- 开发口服可用的和选择性蛋白酶抑制剂仍然是药物发现的重大障碍.
研究的目的:
- 设计,合成和评估新型皮相模性宏循环作为共价血清蛋白酶抑制剂.
- 为了克服与线性相关的药理动力学和代谢限制.
主要方法:
- 侧链循环化宏循环的合理设计和合成,其中包含一个电友基弹头.
- 对抑制剂的强度,对向蛋白酶的选择性 (TMPRSS2,母质酶,素,HGFA),代谢稳定性和药理动力学性质的评估.
- 用X射线晶体学来确定抑制剂与基蛋白酶的结合模式.
主要成果:
- 对TMPRSS2,母质酶,素和HGFA的强效和选择性抑制剂的鉴定.
- 与线性相比,证明了较好的代谢稳定性和药物动力学概况.
- X射线晶体结构揭示了一种意想不到的结合形状,用于乙烯循环三 (VD4162).
- 循环双乙醇VD5123在小鼠中表现出优异的PK特性,半衰期为4.5小时,暴露时间长.
结论:
- 新型循环三基架为开发蛋白酶抑制剂提供了一个多功能平台.
- 这一策略有效地解决了线性的局限性,推动了蛋白酶抑制剂药物发现.
- 开发的宏循环代表了针对氨酸蛋白酶的治疗应用的有希望的候选人.
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