Institute of Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Chem Biol Drug Des. 2011 Nov;78(5):887-92. doi: 10.1111/j.1747-0285.2011.01207.x. Epub 2011 Sep 26.
Linear peptides suffer from poor pharmacokinetic and pharmacodynamic properties. Peptidomimetics are designed to overcome these pharmacological drawbacks while maintaining the biological effects of the parent peptides. Aza-peptides, in which an alpha carbon is replaced with nitrogen, are promising peptidomimetic analogs; however, little is known about the stability of these analogs toward enzymatic degradation. We performed systematic aza and N-methyl scans of a PKB/Akt inhibitor, PTR6154. We evaluated the stability of the aza-scan and N-methyl scan libraries toward enzymatic degradation by trypsin/chymotrypsin. Our results indicate that the modification site is important for metabolic stability and that aza-peptides have a more global effect than N-methylation, affecting cleavage sites distant from the modification site.
线性肽具有较差的药代动力学和药效学性质。肽模拟物旨在克服这些药理缺陷，同时保持母体肽的生物学效应。其中一个α碳原子被氮取代的氮杂肽是很有前途的肽模拟物；然而，对于这些类似物对酶降解的稳定性知之甚少。我们对 PKB/Akt 抑制剂 PTR6154 进行了系统的氮杂和 N-甲基扫描。我们通过胰蛋白酶/糜蛋白酶评估了氮杂扫描和 N-甲基扫描文库对酶降解的稳定性。结果表明，修饰部位对代谢稳定性很重要，并且氮杂肽的影响比 N-甲基化更广泛，会影响远离修饰部位的切割位点。
